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  • 1.
    Abraham-Nordling, Mirna
    et al.
    Karolinska institutet.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Nordling, Erik
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Model of the complex of Parathyroid hormone-2receptor and Tuberoinfundibular peptide of39 residues2010In: BMC Reseach Notes, ISSN 1756-0500, Vol. 3, no 270Article in journal (Refereed)
    Abstract [en]

    Background

    We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.

    Findings

    In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation.

    Conclusions

    A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

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  • 2.
    Almgren, Malin
    et al.
    Karolinska Institutet.
    Nyengaard, Jens R
    Aarhus University.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Lavebratt, Catharina
    Karolinska Institutet.
    Carbamazepine protects against neuronal hyperplasia and abnormal gene expression in the megencephaly mouse2008In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 32, p. 364-376Article in journal (Refereed)
  • 3.
    Almstedt, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Karlsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II2004In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 342, no 2, p. 619-633Article in journal (Refereed)
    Abstract [en]

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.

  • 4.
    Berggren, Karl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics . Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    20 years in HPC 1989-20092009Other (Other (popular science, discussion, etc.))
  • 5.
    Bresel, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    GenomeLKPG: A comprehensive proteome sequencedatabase for taxonomy studies2008Article in journal (Refereed)
    Abstract [en]

    Background: In order to perform taxonomically unbiased analyses of protein relationships, there is a need ofcomplete proteomes rather than databases with bias towards well characterized protein families. However, nocomprehensive resource of completed proteomes is currently available. Instead, the proteomes need to be down-loaded manually from di®erent servers, all using different filename conventions and fasta header formats.

    Results: We have developed a semi-automatic algorithm that retrieves complete proteomes from multiple FTP-servers and maps the species-speci¯c sequence entries to the NCBI taxonomy. The compiled data is provided ina sequence database named genomeLKPG.

    Conclusions: The usefulness of genomeLKPG is proven in several published taxonomical studies.

  • 6.
    Bresell, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Characterization of oligopeptide patterns in large protein sets2007In: BMC Genomics, E-ISSN 1471-2164, Vol. 8, no 346, p. 1-15Article in journal (Refereed)
    Abstract [en]

    Background: Recent sequencing projects and the growth of sequence data banks enable oligopeptide patterns to be characterized on a genome or kingdom level. Several studies have focused on kingdom or habitat classifications based on the abundance of short peptide patterns. There have also been efforts at local structural prediction based on short sequence motifs. Oligopeptide patterns undoubtedly carry valuable information content. Therefore, it is important to characterize these informational peptide patterns to shed light on possible new applications and the pitfalls implicit in neglecting bias in peptide patterns.

    Results: We have studied four classes of pentapeptide patterns (designated POP, NEP, ORP and URP) in the kingdoms archaea, bacteria and eukaryotes. POP are highly abundant patterns statistically not expected to exist; NEP are patterns that do not exist but are statistically expected to; ORP are patterns unique to a kingdom; and URP are patterns excluded from a kingdom. We used two data sources: the de facto standard of protein knowledge Swiss-Prot, and a set of 386 completely sequenced genomes. For each class of peptides we looked at the 100 most extreme and found both known and unknown sequence features. Most of the known sequence motifs can be explained on the basis of the protein families from which they originate.

    Conclusion: We find an inherent bias of certain oligopeptide patterns in naturally occurring proteins that cannot be explained solely on the basis of residue distribution in single proteins, kingdoms or databases. We see three predominant categories of patterns: (i) patterns widespread in a kingdom such as those originating from respiratory chain-associated proteins and translation machinery; (ii) proteins with structurally and/or functionally favored patterns, which have not yet been ascribed this role; (iii) multicopy species-specific retrotransposons, only found in the genome set. These categories will affect the accuracy of sequence pattern algorithms that rely mainly on amino acid residue usage. Methods presented in this paper may be used to discover targets for antibiotics, as we identify numerous examples of kingdom-specific antigens among our peptide classes. The methods may also be useful for detecting coding regions of genes.

  • 7.
    Bresell, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Using SVM and tripeptide patterns to detect translated introns2007In: BMC Bioinformatics, E-ISSN 1471-2105Article in journal (Refereed)
  • 8.
    Bresell, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Servenius, Bo
    Biological Sciences, AstraZeneca R&D Lund, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Ontology annotation treebrowser: an interactive tool where the complementarity of medical subject headings and gene ontology improves the interpretation of gene lists2006In: Applied Bioinformatics, ISSN 1175-5636, Vol. 5, no 4, p. 225-236Article in journal (Refereed)
    Abstract [en]

    Gene expression and proteomics analysis allow the investigation of thousands of biomolecules in parallel. This results in a long list of interesting genes or proteins and a list of annotation terms in the order of thousands. It is not a trivial task to understand such a gene list and it would require extensive efforts to bring together the overwhelming amounts of associated information from the literature and databases. Thus, it is evident that we need ways of condensing and filtering this information. An excellent way to represent knowledge is to use ontologies, where it is possible to group genes or terms with overlapping context, rather than studying one-dimensional lists of keywords. Therefore, we have built the ontology annotation treebrowser (OAT) to represent, condense, filter and summarise the knowledge associated with a list of genes or proteins.

    The OAT system consists of two disjointed parts; a MySQL® database named OATdb, and a treebrowser engine that is implemented as a web interface. The OAT system is implemented using Perl scripts on an Apache web server and the gene, ontology and annotation data is stored in a relational MySQL® database. In OAT, we have harmonized the two ontologies of medical subject headings (MeSH) and gene ontology (GO), to enable us to use knowledge both from the literature and the annotation projects in the same tool. OAT includes multiple gene identifier sets, which are merged internally in the OAT database. We have also generated novel MeSH annotations by mapping accession numbers to MEDLINE entries.

    The ontology browser OAT was created to facilitate the analysis of gene lists. It can be browsed dynamically, so that a scientist can interact with the data and govern the outcome. Test statistics show which branches are enriched. We also show that the two ontologies complement each other, with surprisingly low overlap, by mapping annotations to the Unified Medical Language System®.

    We have developed a novel interactive annotation browser that is the first to incorporate both MeSH and GO for improved interpretation of gene lists. With OAT, we illustrate the benefits of combining MeSH and GO for understanding gene lists. OAT is available as a public web service at: http://www.ifm.liu.se/bioinfo/oat

  • 9.
    Bresell, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Weinander, Rolf
    Department of Medicine, Division of Rheumatology Unit, Karolinska Institutet, Stockholm.
    Wiklund, Ronney
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Eriksson, Jan
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Jansson, Christer
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Jakobsson, Per-Johan
    Department of Medicine, Division of Rheumatology Unit, Karolinska Institutet, Stockholm.
    Morgenstern, Ralf
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Lundqvist, Gerd
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Raza, Haider
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Shimoji, Miyuki
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Sun, Tie-Hua
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Balk, Lennart
    Stockholm Marine Research Centre, University of Stockholm.
    Bioinformatic and enzymatic characterization of the MAPEG superfamily2005In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 272, no 7, p. 1688-1703Article in journal (Refereed)
    Abstract [en]

    The membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily includes structurally related membrane proteins with diverse functions of widespread origin. A total of 136 proteins belonging to the MAPEG superfamily were found in database and genome screenings. The members were found in prokaryotes and eukaryotes, but not in any archaeal organism. Multiple sequence alignments and calculations of evolutionary trees revealed a clear subdivision of the eukaryotic MAPEG members, corresponding to the six families of microsomal glutathione transferases (MGST) 1, 2 and 3, leukotriene C4 synthase (LTC4), 5-lipoxygenase activating protein (FLAP), and prostaglandin E synthase. Prokaryotes contain at least two distinct potential ancestral subfamilies, of which one is unique, whereas the other most closely resembles enzymes that belong to the MGST2/FLAP/LTC4 synthase families. The insect members are most similar to MGST1/prostaglandin E synthase. With the new data available, we observe that fish enzymes are present in all six families, showing an early origin for MAPEG family differentiation. Thus, the evolutionary origins and relationships of the MAPEG superfamily can be defined, including distinct sequence patterns characteristic for each of the subfamilies. We have further investigated and functionally characterized representative gene products from Escherichia coli, Synechocystis sp., Arabidopsis thaliana and Drosophila melanogaster, and the fish liver enzyme, purified from pike (Esox lucius). Protein overexpression and enzyme activity analysis demonstrated that all proteins catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione. The E. coli protein displayed glutathione transferase activity of 0.11 µmol·min−1·mg−1 in the membrane fraction from bacteria overexpressing the protein. Partial purification of the Synechocystis sp. protein yielded an enzyme of the expected molecular mass and an N-terminal amino acid sequence that was at least 50% pure, with a specific activity towards 1-chloro-2,4-dinitrobenzene of 11 µmol·min−1·mg−1. Yeast microsomes expressing the Arabidopsis enzyme showed an activity of 0.02 µmol·min−1·mg−1, whereas the Drosophila enzyme expressed in E. coli was highly active at 3.6 µmol·min−1·mg−1. The purified pike enzyme is the most active MGST described so far with a specific activity of 285 µmol·min−1·mg−1. Drosophila and pike enzymes also displayed glutathione peroxidase activity towards cumene hydroperoxide (0.4 and 2.2 µmol·min−1·mg−1, respectively). Glutathione transferase activity can thus be regarded as a common denominator for a majority of MAPEG members throughout the kingdoms of life whereas glutathione peroxidase activity occurs in representatives from the MGST1, 2 and 3 and PGES subfamilies.

  • 10.
    Bzhalava, David
    et al.
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Ekström, Johanna
    Lund University, Malmö.
    Lysholm, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Hultin, Emilie
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Faust, Helena
    Lund University, Malmö.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Lehtinen, Matti
    National Institute for Health and Welfare, Oulu, Finland.
    de Villiers, Ethel-Michele
    Deutsches Krebsforschungszentrum, Heidelberg, Germany.
    Dillner, Joakim
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Phylogenetically diverse TT virus viremia among pregnant women2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 432, no 2, p. 427-434Article in journal (Refereed)
    Abstract [en]

    Infections during pregnancy have been suggested to be involved in childhood leukemias. We used high-throughput sequencing to describe the viruses most readily detectable in serum samples of pregnantwomen. Serum DNA of 112 mothers to leukemic children was amplified using whole genome amplification. Sequencing identified one TTvirus (TTV) isolate belonging to a known type and two putatively new TTVs. For 22 mothers, we also performed TTV amplification by general primer PCR before sequencing. This detected 39 TTVs, two of which were identical to the TTVs found after whole genome amplification.

    Altogether, we found 40 TTV isolates, 29 of which were putatively new types (similarities ranging from 89% to 69%). In conclusion, high throughput sequencing is useful to describe the known or unknown viruses that are present in serum samples of pregnantwomen.

  • 11.
    Bzhalava, Davit
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Johansson, Hanna
    Lund University, Malmö, Sweden.
    Ekstrom, Johanna
    Karolinska Institutet, Stockholm, Sweden.
    Faust, Helena
    Lund University, Malmö, Sweden.
    Moller, Birgitta
    Karolinska Institutet, Stockholm, Sweden.
    Eklund, Carina
    Karolinska Institutet, Stockholm, Sweden.
    Nordin, Peter
    Läkarhuset, Gothenburg, Sweden.
    Stenquist, Bo
    University of Gothenburg, Sweden.
    Paoli, John
    University of Gothenburg, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Forslund, Ola
    Lund University, Malmö, Sweden.
    Dillner, Joakim
    Karolinska Institutet, Stockholm, Sweden.
    Unbiased Approach for Virus Detection in Skin Lesions2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 6Article in journal (Refereed)
    Abstract [en]

    To assess presence of virus DNA in skin lesions, swab samples from 82 squamous cell carcinomas of the skin (SCCs), 60 actinic keratoses (AKs), paraffin-embedded biopsies from 28 SCCs and 72 kerathoacanthomas (KAs) and fresh-frozen biopsies from 92 KAs, 85 SCCs and 92 AKs were analyzed by high throughput sequencing (HTS) using 454 or Ion Torrent technology. We found total of 4,284 viral reads, out of which 4,168 were Human Papillomavirus (HPV)-related, belonging to 15 known (HPV8, HPV12, HPV20, HPV36, HPV38, HPV45, HPV57, HPV59, HPV104, HPV105, HPV107, HPV109, HPV124, HPV138, HPV147), four previously described putative (HPV 915 F 06 007 FD1, FA73, FA101, SE42) and two putatively new HPV types (SE46, SE47). SE42 was cloned, sequenced, designated as HPV155 and found to have 76% similarity to the most closely related known HPV type. In conclusion, an unbiased approach for viral DNA detection in skin tumors has found that, although some new putative HPVs were found, known HPV types constituted most of the viral DNA.

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  • 12.
    Carlsson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Investigating protein variants using structural calculation techniques2012In: Homology Modeling: Methods and Protocols / [ed] Andrew J. W. Orry and Ruben Abagyan, Springer, 2012, Vol. 857, p. 313-330Chapter in book (Other academic)
    Abstract [en]

    Knowledge about protein tertiary structure can guide experiments, assist in the understanding of structure-function relationships, and aid the design of new therapeutics for disease. Homology modeling is an in silico method that predicts the tertiary structure of an amino acid sequence based on a homologous experimentally determined structure. In, Homology Modeling: Methods and Protocols experts in the field describe each homology modeling step from first principles, provide case studies for challenging modeling targets and describe methods for the prediction of how other molecules such as drugs can interact with the protein. Written in the highly successful Methods in Molecular Biology series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Thorough and intuitive, Homology Modeling: Methods and Protocols guides scientists in the available homology modeling methods.

  • 13.
    Carlsson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Soussi, Thierry
    Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Investigation and prediction of the severity of p53 mutants using parameters from structural calculations2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 15, p. 4142-4155Article in journal (Refereed)
    Abstract [en]

    A method has been developed to predict the effects of mutations in the p53 cancer suppressor gene. The new method uses novel parameters combined with previously established parameters. The most important parameter is the stability measure of the mutated structure calculated using molecular modelling. For each mutant, a severity score is reported, which can be used for classification into deleterious and nondeleterious. Both structural features and sequence properties are taken into account. The method has a prediction accuracy of 77% on all mutants and 88% on breast cancer mutations affecting WAF1 promoter binding. When compared with earlier methods, using the same dataset, our method clearly performs better. As a result of the severity score calculated for every mutant, valuable knowledge can be gained regarding p53, a protein that is believed to be involved in over 50% of all human cancers.

  • 14.
    Carlsson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Vahdat Shariatpanahi, Aida
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulationsManuscript (preprint) (Other academic)
    Abstract [en]

    Amyloidosis is the largest group among the protein misfolding diseases, and includes well known diseases such as Alzheimer’s disease and type 2 diabetes. In the latter, islet amyloid is present in the pancreas in almost all individuals. Today, more than 25 different proteins have been isolated from amyloid deposits in human. Even though these proteins differ in size, charge and sequence they all have the capacity to assemble in to fibrillar structures with inseparable morphological appearance. Therefore, it can be assumed that the fibril process is based upon principles that are general for all proteins and knowledge derived from one protein can be used for other amyloid proteins. In this paper, we study the process of amyloid formation in parts of islet amyloid polypeptide (residues 18-29 and 11-37) by analyzing mutations using three different in silico methods. Finally, we use the methods to predict the amyloidogenic properties of the native IAPP and 16 variants thereof and compare the result with in vitro measurements. Using a consensus prediction of the three methods we managed to correctly classify all but two peptides. We have also given further evidence to the importance of S28P for inhibiting amyloid fibre formation, found evidence for antiparallel stacking, and identified important regions for beta sheet stability.

  • 15.
    Carlsson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Wedell, Anna
    Department of Molecular Medicine and Surgery, CMM:02, Karolinska Institutet/Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    A structural model of human steroid 11-betahydroxylase,CYP11B1, used to predict consequences of mutations2009Article in journal (Other academic)
    Abstract [en]

    A prediction method has been developed to estimate the severity of amino acid residue exchanges in human steroid 11-beta-hydroxylase, CYP11B1, due to mutations in the corresponding gene. The prediction is based both on structural and on sequence dependent parameters. The method uses two approaches; one with general molecular property weights and one with a consensus voting strategy based upon distribution of molecular properties, which does not require any training. Both methods are tested on known mutations in CYP11B1 and result in 85% prediction accuracy. The consensus voting method is then further evaluated on 9 proteins with an average of 81% prediction accuracy. A server utilizing the results from the consensus voting on CYP11B1 is provided where the user can extract information about new mutants. A similar server is also provided for mutants in human steroid 21-hydroxylase (CYP21).

  • 16.
    Cederlund, Ella
    et al.
    Karolinska Institute.
    Hedlund, Joel
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Hjelmqvist, Lars
    Karolinska Institute.
    Jonsson, Andreas
    Karolinska Institute.
    Shafqat, Jawed
    Karolinska Institute.
    Norin, Annika
    Karolinska Institute.
    Keung, Wing-Ming
    Harvard University.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Jornvall, Hans
    Karolinska Institute.
    Characterization of new medium-chain alcohol dehydrogenases adds resolution to duplications of the class I/III and the sub-class I genes2011In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 191, no 03-janArticle in journal (Refereed)
    Abstract [en]

    Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.

  • 17.
    Hederos, Sofia
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Tegler, Lotta
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Viljanen, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kerstin S., Broo
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    A Promiscuous Glutathione Transferase Transformed into a Selective Thiolester Hydrolase2006In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 1, p. 90-97Article in journal (Refereed)
  • 18.
    Hedlund, Joel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Cantoni, Roberto
    Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
    Baltscheffsky, Margareta
    Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
    Baltscheffsky, Herrick
    Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics.
    Analysis of ancient sequence motifs in the H+ -PPase family2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, p. 5183-5193Article in journal (Refereed)
    Abstract [en]

    The unique family of membrane-bound proton-pumping inorganic pyrophosphatases, involving pyrophosphate as the alternative to ATP, was investigated by characterizing 166 members of the UniProtKB ⁄ Swiss-Prot + UniProtKB ⁄TrEMBL databases and available completed genomes, using sequence comparisons and a hidden Markov model based upon a conserved 57-residue region in the loop between transmembrane segments 5 and 6. The hidden Markov model was also used to search the approximately one million sequences recently reported from a large-scale sequencing project of organisms in the Sargasso Sea, resulting in additional 164 partial pyrophosphatase sequences. The strongly conserved 57-residue region was found to contain two nonapeptidyl sequences, mainly consisting of the four ‘very early’ proteinaceous amino acid residues Gly, Ala, Val and Asp, compatible with an ancient origin of the inorganic pyrophosphatases. The nonapeptide patterns have charged amino acid residues at positions 1, 5 and 9, are apparent binding sites for the substrate and parts of the active site, and were shown to be so specific for these enzymes that they can be used for functional assignments of unannotated genomes.

  • 19.
    Hedlund, Joel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Johansson, Jan
    Dept of Anatomy, Physiology and Biochemistry, The Biomedical Centre, Box 575, S-751 23 Uppsala, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    BRICHOS - a superfamily of multidomain proteins with diverse functions.2009In: BMC research notes, ISSN 1756-0500, Vol. 2, p. 180-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: The BRICHOS domain has been found in 8 protein families with a wide range of functions and a variety of disease associations, such as respiratory distress syndrome, dementia and cancer. The domain itself is thought to have a chaperone function, and indeed three of the families are associated with amyloid formation, but its structure and many of its functional properties are still unknown. FINDINGS: The proteins in the BRICHOS superfamily have four regions with distinct properties. We have analysed the BRICHOS proteins focusing on sequence conservation, amino acid residue properties, native disorder and secondary structure predictions. Residue conservation shows large variations between the regions, and the spread of residue conservation between different families can vary greatly within the regions. The secondary structure predictions for the BRICHOS proteins show remarkable coherence even where sequence conservation is low, and there seems to be little native disorder. CONCLUSIONS: The greatly variant rates of conservation indicates different functional constraints among the regions and among the families. We present three previously unknown BRICHOS families; group A, which may be ancestral to the ITM2 families; group B, which is a close relative to the gastrokine families, and group C, which appears to be a truly novel, disjoint BRICHOS family. The C-terminal region of group C has nearly identical sequences in all species ranging from fish to man and is seemingly unique to this family, indicating critical functional or structural properties.

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  • 20.
    Hedlund, Joel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Jörnvall, Hans
    Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Subdivision of the MDR superfamily of medium-chain dehydrogenases/reductases through iterative hidden Markov model refinement2010In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 11, p. 534-Article in journal (Refereed)
    Abstract [en]

    Backgroun: The Medium-chain Dehydrogenases/Reductases (MDR) form a protein superfamily whose size and complexity defeats traditional means of subclassification; it currently has over 15000 members in the databases, the pairwise sequence identity is typically around 25%, there are members from all kingdoms of life, the chain-lengths vary as does the oligomericity, and the members are partaking in a multitude of biological processes. There are profile hidden Markov models (HMMs) available for detecting MDR superfamily members, but none for determining which MDR family each protein belongs to. The current torrential influx of new sequence data enables elucidation of more and more protein families, and at an increasingly fine granularity. However, gathering good quality training data usually requires manual attention by experts and has therefore been the rate limiting step for expanding the number of available models.

    Result: We have developed an automated algorithm for HMM refinement that produces stable and reliable models for protein families. This algorithm uses relationships found in data to generate confident seed sets. Using this algorithm we have produced HMMs for 86 distinct MDR families and 34 of their subfamilies which can be used in automated annotation of new sequences. We find that MDR forms with 2 Zn2+ ions in general are dehydrogenases, while MDR forms with no Zn2+ in general are reductases. Furthermore, in Bacteria MDRs without Zn2+ are more frequent than those with Zn2+, while the opposite is true for eukaryotic MDRs, indicating that Zn2+ has been recruited into the MDR superfamily after the initial life kingdom separations. We have also developed a web site http://mdr-enzymes.org webcite that provides textual and numeric search against various characterised MDR family properties, as well as sequence scan functions for reliable classification of novel MDR sequences.

    Conclusion: Our method of refinement can be readily applied to create stable and reliable HMMs for both MDR and other protein families, and to confidently subdivide large and complex protein superfamilies. HMMs created using this algorithm correspond to evolutionary entities, making resolution of overlapping models straightforward. The implementation and support scripts for running the algorithm on computer clusters are available as open source software, and the database files underlying the web site are freely downloadable. The web site also makes our findings directly useful also for non-bioinformaticians.

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  • 21.
    Hellgren, M.
    et al.
    Dept. of Medical Biochemistry and Biophysics Karolinska Inst. Stockholm.
    Strömberg, P.
    Dept. of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm.
    Matras, S.
    Dept. of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, Spanien.
    Farres, J.
    Dept. of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, Spanien.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Parés, X.
    Dept. of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, Spanien.
    Höög, J.-O.
    Dept. of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm.
    Alcohol dehydrogenase 2 is major hepatic enzyme for human retinol metabolism2007In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 64, p. 498-505Article in journal (Refereed)
    Abstract [en]

      

  • 22.
    Hellgren, Mikko
    et al.
    Karolinska Institute.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Ostberg, Linus J
    Karolinska Institute.
    Staab, Claudia A
    Karolinska Institute.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Hoog, Jan-Olov
    Karolinska Institute.
    Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 32010In: CELLULAR AND MOLECULAR LIFE SCIENCES, ISSN 1420-682X, Vol. 67, no 17, p. 3005-3015Article in journal (Refereed)
    Abstract [en]

    Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k (cat)/K (m) values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.

  • 23.
    Hellgren, Mikko
    et al.
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Östberg, Linus
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Staab, Claudia A.
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Höög, Jan-Olov
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Virtual screening for ligands to human alcohol dehydrogenase 3Manuscript (preprint) (Other academic)
    Abstract [en]

    Alcohol dehydrogenase 3 (ADH3) has been suggested a role in nitric oxide homeostasis due to its function as a S-nitrosoglutathione (GSNO) reductase. This has requested a modulator of the ADH3 activity for control of GSNO levels. Today virtual screenings are frequently used in drug discovery to dock and rank a large number of compounds. With molecular dockings of more than 40,000 compounds into the active site pocket of human ADH3 we ranked compounds with a novel method. Six top ranked compounds that were not known to interact with ADH3 were tested in vitro, where two showed substrate activity (9-decen-1-ol and dodecyltetraglycol), two showed inhibition capacity (deoxycholic acid and doxorubicin) and two did not have any detectable effect. For the substrates, site specific interactions and calculated binding scoring energies were determined with an extended docking simulation including flexible side chains of amino acids residues. The binding scoring energies correlated well with the logarithm of the substrates kcat over Km values. Furthermore, with these computational and experimental data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs and in addition deoxycholic acids.

  • 24.
    Hennig, Janosch
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Bresell, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Sandberg, Martina
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Hennig, Klaus D. M.
    Gabriele von Bülow Gymnasium, Berlin.
    Wahren-Herlenius, Marie
    Karolinska Hospital.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    The fellowship of the RING: The RING-B-box linker region (RBL) interacts with the RING in TRIM21/Ro52, contributes to an autoantigenic epitope in Sjögren's syndrome, and is an integral and conserved region in TRIM proteins2008In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 377, no 2, p. 431-449Article in journal (Refereed)
    Abstract [en]

    Ro52 is a major autoantigen that is targeted in the autoimmune disease Sjögren syndrome and belongs to the tripartite motif (TRIM) protein family. Disease-related antigenic epitopes are mainly found in the coiled-coil domain of Ro52, but one such epitope is located in the Zn2+-binding region, which comprises an N-terminal RING followed by a B-box, separated by a ∼40-residue linker peptide. In the present study, we extend the structural, biophysical, and immunological knowledge of this RING-B-box linker (RBL) by employing an array of methods. Our bioinformatic investigations show that the RBL sequence motif is unique to TRIM proteins and can be classified into three distinct subtypes. The RBL regions of all three subtypes are as conserved as their known flanking domains, and all are predicted to comprise an amphipathic helix. This helix formation is confirmed by circular dichroism spectroscopy and is dependent on the presence of the RING. Immunological studies show that the RBL is part of a conformation-dependent epitope, and its antigenicity is likewise dependent on a structured RING domain. Recombinant Ro52 RING-RBL exists as a monomer in vitro, and binding of two Zn2+ increases its stability. Regions stabilized by Zn2+ binding are identified by limited proteolysis and matrix-assisted laser desorption/ionization mass spectrometry. Furthermore, the residues of the RING and linker that interact with each other are identified by analysis of protection patterns, which, together with bioinformatic and biophysical data, enabled us to propose a structural model of the RING-RBL based on modeling and docking experiments. Sequence similarities and evolutionary sequence patterns suggest that the results obtained from Ro52 are extendable to the entire TRIM protein family.

  • 25.
    Henriksson, M.
    et al.
    Karolinska Institutet.
    Nordling, E.
    Karolinska Institutet.
    Melles, E.
    Karolinska Institutet.
    Shafqat, J.
    Karolinska Institutet.
    Ståhlberg, M.
    Karolinska Institutet.
    Ekberg, K.
    Karolinska Hospital.
    Persson, Bengt
    Karolinska Institutet.
    Bergman, T.
    Karolinska Institutet.
    Wahren, J.
    Karolinska Hospital.
    Johansson, J.
    Karolinska Institutet.
    Jörnvall, H.
    Karolinska Institutet.
    Separate functional features of proinsulin C-peptide2005In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 62, no 15, p. 1772-1778Article in journal (Refereed)
    Abstract [en]

    Proinsulin C-peptide influences a number of physiological parameters in addition to its well-established role in the parent proinsulin molecule. It is of interest as a candidate for future co-replacement therapy with insulin for patients with diabetes mellitus type 1, but specific receptors have not been identified and additional correlation with functional effects is desirable. Based on comparisons of 22 mammalian proinsulin variants, we have constructed analogues for activity studies, choosing phosphorylation of mitogen-activated protein kinases (MAPKs) in Swiss 3T3 fibroblasts for functional measurements. In this manner, we find that effective phosphorylation of MAPKs is promoted by the presence of conserved glutamic acid residues at positions 3, 11 and 27 of C-peptide and by the presence of helix-promoting residues in the N-terminal segment. Previous findings have ascribed functional roles to the C-terminal pentapeptide segment, and all results combined therefore now show the importance of different segments, suggesting that C-peptide interactions are complex or multiple. © Birkhäuser Verlag, 2005.

  • 26.
    Hosia, W.
    et al.
    Dept. of Med. Biochem. and Biophys., Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Bark, N.
    Dept. of Med. Biochem. and Biophys., Karolinska Institutet, S-171 77 Stockholm, Sweden, Department of Clinical Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Liepinsh, E.
    Dept. of Med. Biochem. and Biophys., Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Tjernberg, A.
    Dept. of Med. Biochem. and Biophys., Karolinska Institutet, S-171 77 Stockholm, Sweden, Department of Structural Chemistry, Biovitrum AB, S-112 76 Stockholm, Sweden.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Hallen, D.
    Hallén, D., Department of Structural Chemistry, Biovitrum AB, S-112 76 Stockholm, Sweden.
    Thyberg, J.
    Dept. of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Johansson, J.
    Dept. of Med. Biochem. and Biophys., Karolinska Institutet, S-171 77 Stockholm, Sweden, Department of Molecular Biosciences, Swed. Univ. of Agricultural Sciences, Biomedical Center, S-751 23 Uppsala, Sweden.
    Tjernberg, L.
    Department of Neurotec, Karolinska Institutet, S-141 57 Huddinge, Sweden.
    Folding into a ß-Hairpin Can Prevent Amyloid Fibril-Formation2004In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 43, no 16, p. 4655-4661Article in journal (Refereed)
    Abstract [en]

    The tetrapeptide KFFE is one of the shortest amyloid fibril-forming peptides described. Herein, we have investigated how the structural environment of this motif affects polymerization. Using a turn motif (YNGK) or a less rigid sequence (AAAK) to fuse two KFFE tetrapeptides, we show by several biophysical methods that the amyloidogenic properties are strongly dependent on the structural environment. The dodecapeptide KFFEAAAKKFFE forms abundant thick fibril bundles. Freshly dissolved KFFEAAAKKFFE is monomeric and shows mainly disordered secondary structure, as evidenced by circular dichroism, NMR spectroscopy, hydrogen/deuterium exchange measurements, and molecular modeling studies. In sharp contrast, the dodecapeptide KFFEYNGKKFFE does not form fibrils but folds into a stable ß-hairpin. This structure can oligomerize into a stable 12-mer and multiples thereof, as shown by size exclusion chromatography, sedimentation analysis, and electrospray mass spectrometry. These data indicate that the structural context in which a potential fibril forming sequence is present can prevent fibril formation by favoring self-limiting oligomerization over polymerization.

  • 27.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Olsson, Anette
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Storm, Petter
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Margolin, Sara
    Department of Oncology, Karolinska University Hospital/ Södersjukhuset, Stockholm, Sweden.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindblom, Annika
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer2007In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 106, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

  • 28.
    Joannin, Nicolas
    et al.
    Karolinska Institute.
    Kallberg, Yvonne
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Wahlgren, Mats
    Karolinska Institute.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    RSpred, a set of Hidden Markov Models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum2011In: BMC Genomics, E-ISSN 1471-2164, Vol. 12, no 119Article in journal (Refereed)
    Abstract [en]

    Background: Many parasites use multicopy protein families to avoid their hosts immune system through a strategy called antigenic variation. RIFIN and STEVOR proteins are variable surface antigens uniquely found in the malaria parasites Plasmodium falciparum and P. reichenowi. Although these two protein families are different, they have more similarity to each other than to any other proteins described to date. As a result, they have been grouped together in one Pfam domain. However, a recent study has described the sub-division of the RIFIN protein family into several functionally distinct groups. These sub-groups require phylogenetic analysis to sort out, which is not practical for large-scale projects, such as the sequencing of patient isolates and meta-genomic analysis. Results: We have manually curated the rif and stevor gene repertoires of two Plasmodium falciparum genomes, isolates DD2 and HB3. We have identified 25% of mis-annotated and similar to 30 missing rif and stevor genes. Using these data sets, as well as sequences from the well curated reference genome (isolate 3D7) and field isolate data from Uniprot, we have developed a tool named RSpred. The tool, based on a set of hidden Markov models and an evaluation program, automatically identifies STEVOR and RIFIN sequences as well as the sub-groups: A-RIFIN, B-RIFIN, B1-RIFIN and B2-RIFIN. In addition to these groups, we distinguish a small subset of STEVOR proteins that we named STEVOR-like, as they either differ remarkably from typical STEVOR proteins or are too fragmented to reach a high enough score. When compared to Pfam and TIGRFAMs, RSpred proves to be a more robust and more sensitive method. We have applied RSpred to the proteomes of several P. falciparum strains, P. reichenowi, P. vivax, P. knowlesi and the rodent malaria species. All groups were found in the P. falciparum strains, and also in the P. reichenowi parasite, whereas none were predicted in the other species. Conclusions: We have generated a tool for the sorting of RIFIN and STEVOR proteins, large antigenic variant protein groups, into homogeneous sub-families. Assigning functions to such protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. RSpred removes the need for complicated and time consuming phylogenetic analysis methods. It will benefit both research groups sequencing whole genomes as well as others working with field isolates. RSpred is freely accessible via http://www.ifm.liu.se/bioinfo/.

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  • 29.
    Jornvall, H.
    et al.
    Jörnvall, H., Dept. of Med. Biochem./Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nordling, E.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Multiplicity of eukaryotic ADH and other MDR forms2003In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 143-144, p. 255-261Conference paper (Other academic)
    Abstract [en]

    Eukaryotic genomes code for at least eight medium-chain dehydrogenases/reductases (MDR) enzyme families of two types, with and without Zn2+ at the active site. Four families have Zn2+: 'Dimeric alcohol dehydrogenases (ADHs)' (including liver ADHs), 'Tetrameric ADHs' (including the yeast ADHs), 'Cinnamyl ADHs' and 'Polyol DHs'. In the human genome, there are minimally 23 MDR genes, but the list is still growing from further interpretations. Of these, seven genes on chromosome 4 (and three pseudogenes) represent the ADH classes in the gene order IV, I?, Iß, Ia, V, II and III. The lineages leading to human ADH establish five levels of divergence, with nodes at the MDR/short-chain dehydrogenases/reductases (SDR), dimer/tetramer, class III/non-III, further class, and intraclass levels of divergence. These multiplicities allow conclusions on pathways of function for ADHs and suggest this activity to have two roles in addition to its function in metabolism, one of a basic defence nature, the other of regulatory value in higher eukaryotes. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

  • 30.
    Jornvall, Hans
    et al.
    Karolinska Institute, Sweden .
    Hedlund, Joel
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Bergman, Tomas
    Karolinska Institute, Sweden .
    Kallberg, Yvonne
    Karolinska Institute, Sweden .
    Cederlund, Ella
    Karolinska Institute, Sweden .
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Origin and evolution of medium chain alcohol dehydrogenases2013In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 202, no 1-3, p. 91-96Article in journal (Refereed)
    Abstract [en]

    Different lines of alcohol dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication similar to 550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, "Cambrian explosion". Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.

  • 31.
    Jornvall, Hans
    et al.
    Karolinska Institute.
    Hedlund, Joel
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Bergman, Tomas
    Karolinska Institute.
    Oppermann, Udo
    University of Oxford.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Superfamilies SDR and MDR: From early ancestry to present forms. Emergence of three lines, a Zn-metalloenzyme, and distinct variabilities2010In: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ISSN 0006-291X, Vol. 396, no 1, p. 125-130Article in journal (Refereed)
    Abstract [en]

    Two large gene and protein superfamilies, SDR and MDR (short- and medium-chain dehydrogenases/reductases), were originally defined from analysis of alcohol and polyol dehydrogenases. The superfamilies contain minimally 82 and 25 genes, respectively, in humans, minimally 324 and 86 enzyme families when known lines in other organisms are also included, and over 47,000 and 15,000 variants in existing sequence data bank entries. SDR enzymes have one-domain subunits without metal and MDR two-domain subunits without or with zinc, and these three lines appear to have emerged in that order from the universal cellular ancestor. This is compatible with their molecular architectures, present multiplicity, and overall distribution in the kingdoms of life, with SDR also of viral occurrence. An MDR-zinc, when present, is often, but not always, catalytic. It appears also to have a structural role in inter-domain interactions, coenzyme binding and substrate pocket formation, as supported by domain variability ratios and ligand positions. Differences among structural and catalytic zinc ions may be relative and involve several states. Combined, the comparisons trace evolutionary properties of huge superfamilies, with partially redundant enzymes in cellular redox functions.

  • 32.
    Kallberg, Yvonne
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Oppermann, Udo
    University of Oxford.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Classification of the short-chain dehydrogenase/reductase superfamily using hidden Markov models2010In: FEBS JOURNAL, ISSN 1742-464X, Vol. 277, no 10, p. 2375-2386Article in journal (Refereed)
    Abstract [en]

    The short-chain dehydrogenase/reductase (SDR) superfamily now has over 47 000 members, most of which are distantly related, with typically 20-30% residue identity in pairwise comparisons, making it difficult to obtain an overview of this superfamily. We have therefore developed a family classification system, based upon hidden Markov models (HMMs). To this end, we have identified 314 SDR families, encompassing about 31 900 members. In addition, about 9700 SDR forms belong to families with too few members at present to establish valid HMMs. In the human genome, we find 47 SDR families, corresponding to 82 genes. Thirteen families are present in all three domains (Eukaryota, Bacteria, and Archaea), and are hence expected to catalyze fundamental metabolic processes. The majority of these enzymes are of the extended type, in agreement with earlier findings. About half of the SDR families are only found among bacteria, where the classical SDR type is most prominent. The HMM-based classification is used as a basis for a sustainable and expandable nomenclature system.

  • 33.
    Kallberg, Yvonne
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Prediction of coenzyme specificity in dehydrogenases/reductases2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, p. 1177-1184Article in journal (Refereed)
  • 34.
    Kallberg, Yvonne
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Segerstolpe, Åsa
    Stockholm University, Sweden.
    Lackman, Fredrik
    Stockholm University, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Wieslander, Lars
    Stockholm University, Sweden.
    Evolutionary Conservation of the Ribosomal Biogenesis Factor Rbm19/Mrd1: Implications for Function2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 9Article in journal (Refereed)
    Abstract [en]

    Ribosome biogenesis in eukaryotes requires coordinated folding and assembly of a pre-rRNA into sequential pre-rRNA-protein complexes in which chemical modifications and RNA cleavages occur. These processes require many small nucleolar RNAs (snoRNAs) and proteins. Rbm19/Mrd1 is one such protein that is built from multiple RNA-binding domains (RBDs). We find that Rbm19/Mrd1 with five RBDs is present in all branches of the eukaryotic phylogenetic tree, except in animals and Choanoflagellates, that instead have a version with six RBDs and Microsporidia which have a minimal Rbm19/Mrd1 protein with four RBDs. Rbm19/Mrd1 therefore evolved as a multi-RBD protein very early in eukaryotes. The linkers between the RBDs have conserved properties; they are disordered, except for linker 3, and position the RBDs at conserved relative distances from each other. All but one of the RBDs have conserved properties for RNA-binding and each RBD has a specific consensus sequence and a conserved position in the protein, suggesting a functionally important modular design. The patterns of evolutionary conservation provide information for experimental analyses of the function of Rbm19/Mrd1. In vivo mutational analysis confirmed that a highly conserved loop 5-β4-strand in RBD6 is essential for function.

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  • 35.
    Karlsson, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Michael Lindberg, A
    University of Kalmar.
    Rodriguez-Diaz, Jesus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hedlund, Kjell-Olof
    Swedish Institute for Infectious Disease Control.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Svensson , Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Quasispecies dynamics and molecular evolution of human norovirus capsid P region during chronic infection2009In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 90, p. 432-441Article in journal (Refereed)
    Abstract [en]

    In this novel study, we have for the first time identified evolutionarily conserved capsid residues in an individual chronically infected with norovirus (GGII.3). From 2000 to 2003, a total of 147 P1-1 and P2 capsid sequences were sequenced and investigated for evolutionarily conserved and functionally important residues by the evolutionary trace (ET) algorithm. The ET algorithm revealed more absolutely conserved residues (ACR) in the P1-1 domain (47/53, 88 %) as compared with the P2 domain (86/133, 64 %). The capsid P1-1 and P2 domains evolved in time-dependent manner, with a distinct break point observed between autumn/winter of year 2000 (isolates P1, P3 and P5) and spring to autumn of year 2001 (isolates P11, P13 and P15), which presumably coincided with a change of clinical symptoms. Furthermore, the ET analysis revealed a similar receptor-binding pattern as reported for Norwalk and VA387 strains, with the CS-4 and CS-5 patch (Norwalk strain) including residues 329 and 377 and residues 306 and 310, respectively, all being ACR in all partitions. Most interesting was that residues 343, 344, 345, 374, 390 and 391 of the proposed receptor A and B trisaccharide binding site (VA387 strain) within the P2 domain remained ACR in all partitions, presumably because there was no selective advantage to alter the histo blood group antigens (HBGA) receptor binding specificity. In conclusion, this study provides novel insights to the evolutionary process of norovirus during chronic infection.

  • 36.
    Kavanagh, K L
    et al.
    University of Oxford.
    Jornvall, H
    Karolinska Institute.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Oppermann , U
    University of Oxford.
    The SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes2008In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 65, no 24, p. 3895-3906Article in journal (Refereed)
    Abstract [en]

    Short-chain dehydrogenases/reductases (SDRs) constitute a large family of NAD(P)(H)-dependent oxidoreductases, sharing sequence motifs and displaying similar mechanisms. SDR enzymes have critical roles in lipid, amino acid, carbohydrate, cofactor, hormone and xenobiotic metabolism as well as in redox sensor mechanisms. Sequence identities are low, and the most conserved feature is an alpha/beta folding pattern with a central beta sheet flanked by 2 - 3 alpha-helices from each side, thus a classical Rossmannfold motif for nucleotide binding. The conservation of this element and an active site, often with an Asn-Ser-Tyr-Lys tetrad, provides a platform for enzymatic activities encompassing several EC classes, including oxidoreductases, epimerases and lyases. The common mechanism is an underlying hydride and proton transfer involving the nicotinamide and typically an active site tyrosine residue, whereas substrate specificity is determined by a variable C-terminal segment. Relationships exist with bacterial haloalcohol dehalogenases, which lack cofactor binding but have the active site architecture, emphasizing the versatility of the basic fold in also generating hydride transfer-independent lyases. The conserved fold and nucleotide binding emphasize the role of SDRs as scaffolds for an NAD(P)(H) redox sensor system, of importance to control metabolic routes, transcription and signalling.

  • 37.
    Lavebratt, C
    et al.
    Karolinska Institutet.
    Alpman, A
    Karolinska Institutet.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Arner, P
    Karolinska University Hospital.
    Hoffstedt, J
    Karolinska University Hospital.
    Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men2006In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 30, p. 453-459Article in journal (Refereed)
  • 38. Lavebratt, C.
    et al.
    Sengul, S.
    Gu, H.F.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Nordfors, L.
    Östenson, C.-G.
    Efendic, S.
    Arner, P.
    Hoffstedt, J.
    Schalling, M.
    Association study between chromosome 10q26.11 and obesity among Swedish men2005In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 29, no 12, p. 1422-1428Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Proximal chromosome 10q26 was recently linked to waist/hip ratio in European and African-American families. The objective was to investigate whether genomic variation in chromosome 10q26.11 reflects variation in obesity-related clinical parameters in a Swedish population. DESIGN: Genetic association study of single-nucleotide polymorphisms (SNPs) in chromosome 10q26.11 and obesity-related clinical parameters was performed. Obesity was defined as body mass index (BMI)≥30 kg/m2. SUBJECTS: Swedish Caucasians comprising 276 obese and 480 nonobese men, 313 obese and 494 nonobese women, 177 obese and 163 nonobese patients with type 2 diabetes mellitus (T2DM), and 106 obese and 201 nonobese subjects with impaired glucose tolerance (IGT) patients. MEASUREMENTS: Genotypes of 11 SNPs at chromosome 10q26.11, and various obesity-related clinical parameters. RESULTS: Homozygosity of a common haplotype constructed by three SNPs, rs2185937, rs1797 and hCV1402327, covering an interval of 2.7 kb, was suggested to confer an increased risk for obesity of 1.5 among men (P=0.043). The C allele frequency and homozygous genotype frequency of the rs1797 tended to be higher among obese compared to among nonobese men (P=0.017 and 0.020, respectively). The distribution of BMI and diastolic blood pressure was higher among those with the C/C genotype (P=0.022 and 0.0061, respectively). The obese and the nonobese groups were homogeneous over BMI subgroups with regard to rs1797 risk genotype distribution. There was no tendency for association between rs1797 and obesity among neither women nor T2DM nor IGT patients. CONCLUSION: We show support for association between proximal chromosome 10q26.11 and obesity among Swedish men but not women through the analysis of a haplotype encompassing 2.7 kb. © 2005 Nature Publishing Group All rights reserved.

  • 39.
    Lysholm, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Andersson, Bjorn
    Karolinska Institute.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    FAAST: Flow-space Assisted Alignment Search Tool2011In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 12, no 293Article in journal (Refereed)
    Abstract [en]

    Background: High throughput pyrosequencing (454 sequencing) is the major sequencing platform for producing long read high throughput data. While most other sequencing techniques produce reading errors mainly comparable with substitutions, pyrosequencing produce errors mainly comparable with gaps. These errors are less efficiently detected by most conventional alignment programs and may produce inaccurate alignments. less thanbrgreater than less thanbrgreater thanResults: We suggest a novel algorithm for calculating the optimal local alignment which utilises flowpeak information in order to improve alignment accuracy. Flowpeak information can be retained from a 454 sequencing run through interpretation of the binary SFF-file format. This novel algorithm has been implemented in a program named FAAST (Flow-space Assisted Alignment Search Tool). less thanbrgreater than less thanbrgreater thanConclusions: We present and discuss the results of simulations that show that FAAST, through the use of the novel algorithm, can gain several percentage points of accuracy compared to Smith-Waterman-Gotoh alignments, depending on the 454 data quality. Furthermore, through an efficient multi-thread aware implementation, FAAST is able to perform these high quality alignments at high speed. The tool is available at http://www.ifm.liu.se/bioinfo/

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  • 40.
    Lysholm, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Andersson, Björn
    Karolinska Institutet.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    An efficient simulator of 454 data using configurable statistical models2011In: BMC Research Notes, E-ISSN 1756-0500, Vol. 4, no 449Article in journal (Refereed)
    Abstract [en]

    Background

    Roche 454 is one of the major 2nd generation sequencing platforms. The particular characteristics of 454 sequence data   pose new challenges for bioinformatic analyses, e.g. assembly and alignment search   algorithms. Simulation of these data is therefore useful, in order to further assess   how bioinformatic applications and algorithms handle 454 data.

    Findings

    We developed a new application named 454sim for simulation of 454 data at high speed   and accuracy. The program is multi-thread capable and is available as C++ source code   or pre-compiled binaries. Sequence reads are simulated by 454sim using a set of statistical   models for each chemistry. 454sim simulates recorded peak intensities, peak quality   deterioration and it calculates quality values. All three generations of the Roche   454 chemistry ('GS20', 'GS FLX' and 'Titanium') are supported and defined in external   text files for easy access and tweaking.

    Conclusions

    We present a new platform independent application named 454sim. 454sim is generally   200 times faster compared to previous programs and it allows for simple adjustments   of the statistical models. These improvements make it possible to carry out more complex   and rigorous algorithm evaluations in a reasonable time scale.

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  • 41.
    Lysholm, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Wetterbom, Anna
    Karolinska Institutet, Stockholm.
    Lindau, Cecilia
    Karolinska Institutet, Stockholm.
    Darban, Hamid
    Karolinska Institutet, Stockholm.
    Bjerkner, Annelie
    Karolinska Institutet, Stockholm.
    Fahlander, Kristina
    Karolinska Institutet, Stockholm.
    Lindberg, A Michael
    Linnaeus University.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Allander, Tobias
    Karolinska Institutet, Stockholm.
    Andersson, Bjorn
    Karolinska Institutet, Stockholm.
    Characterization of the Viral Microbiome in Patients with Severe Lower Respiratory Tract Infections, Using Metagenomic Sequencing2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed)
    Abstract [en]

    The human respiratory tract is heavily exposed to microorganisms. Viral respiratory tract pathogens, like RSV, influenza and rhinoviruses cause major morbidity and mortality from respiratory tract disease. Furthermore, as viruses have limited means of transmission, viruses that cause pathogenicity in other tissues may be transmitted through the respiratory tract. It is therefore important to chart the human virome in this compartment. We have studied nasopharyngeal aspirate samples submitted to the Karolinska University Laboratory, Stockholm, Sweden from March 2004 to May 2005 for diagnosis of respiratory tract infections. We have used a metagenomic sequencing strategy to characterize viruses, as this provides the most unbiased view of the samples. Virus enrichment followed by 454 sequencing resulted in totally 703,790 reads and 110,931 of these were found to be of viral origin by using an automated classification pipeline. The snapshot of the respiratory tract virome of these 210 patients revealed 39 species and many more strains of viruses. Most of the viral sequences were classified into one of three major families; Paramyxoviridae, Picornaviridae or Orthomyxoviridae. The study also identified one novel type of Rhinovirus C, and identified a number of previously undescribed viral genetic fragments of unknown origin.

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  • 42.
    Melkersson, Kristina
    et al.
    Karolinska Institute, Sweden .
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Evidence for a negative association between schizophrenia and a polymorphism in the insulin receptor substrate-3 (IRS-3) gene2012In: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 33, no 3, p. 321-330Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia. less thanbrgreater than less thanbrgreater thanMETHODS: The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms. less thanbrgreater than less thanbrgreater thanRESULTS: The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05). less thanbrgreater than less thanbrgreater thanCONCLUSION: Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development.

  • 43.
    Moummou, Hanane
    et al.
    University of Toulouse, France .
    Kallberg, Yvonne
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics.
    Brice Tonfack, Libert
    University of Toulouse, France .
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics.
    van der Rest, Benoit
    University of Toulouse, France .
    The Plant Short-Chain Dehydrogenase (SDR) superfamily: genome-wide inventory and diversification patterns2012In: BMC Plant Biology, E-ISSN 1471-2229, Vol. 12, no 219Article in journal (Refereed)
    Abstract [en]

    Background: Short-chain dehydrogenases/reductases (SDRs) form one of the largest and oldest NAD(P)(H) dependent oxidoreductase families. Despite a conserved Rossmann-fold structure, members of the SDR superfamily exhibit low sequence similarities, which constituted a bottleneck in terms of identification. Recent classification methods, relying on hidden-Markov models (HMMs), improved identification and enabled the construction of a nomenclature. However, functional annotations of plant SDRs remain scarce. less thanbrgreater than less thanbrgreater thanResults: Wide-scale analyses were performed on ten plant genomes. The combination of hidden Markov model (HMM) based analyses and similarity searches led to the construction of an exhaustive inventory of plant SDR. With 68 to 315 members found in each analysed genome, the inventory confirmed the over-representation of SDRs in plants compared to animals, fungi and prokaryotes. The plant SDRs were first classified into three major types - classical, extended and divergent - but a minority (10% of the predicted SDRs) could not be classified into these general types (unknown or atypical types). In a second step, we could categorize the vast majority of land plant SDRs into a set of 49 families. Out of these 49 families, 35 appeared early during evolution since they are commonly found through all the Green Lineage. Yet, some SDR families - tropinone reductase-like proteins (SDR65C), ABA2-like-NAD dehydrogenase (SDR110C), salutaridine/menthone-reductase-like proteins (SDR114C), dihydroflavonol 4-reductase-like proteins (SDR108E) and isoflavone-reductase-like (SDR460A) proteins - have undergone significant functional diversification within vascular plants since they diverged from Bryophytes. Interestingly, these diversified families are either involved in the secondary metabolism routes (terpenoids, alkaloids, phenolics) or participate in developmental processes (hormone biosynthesis or catabolism, flower development), in opposition to SDR families involved in primary metabolism which are poorly diversified. less thanbrgreater than less thanbrgreater thanConclusion: The application of HMMs to plant genomes enabled us to identify 49 families that encompass all Angiosperms (higher plants) SDRs, each family being sufficiently conserved to enable simpler analyses based only on overall sequence similarity. The multiplicity of SDRs in plant kingdom is mainly explained by the diversification of large families involved in different secondary metabolism pathways, suggesting that the chemical diversification that accompanied the emergence of vascular plants acted as a driving force for SDR evolution.

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  • 44. Nilsson, J.
    et al.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics.
    von Heijne, G.
    Comparative analysis of amino acid distributions in integral membrane proteins from 107 genomes2005In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 60, no 4, p. 606-616Article in journal (Refereed)
    Abstract [en]

    We have performed a comparative analysis of amino acid distributions in predicted integral membrane proteins from a total of 107 genomes. A procedure for identification of membrane spanning helices was optimized on a homology-reduced data set of 170 multi-spanning membrane proteins with experimentally determined topologies. The optimized method was then used for extraction of highly reliable partial topologies from all predicted membrane proteins in each genome, and the average biases in amino acid distributions between loops on opposite sides of the membrane were calculated. The results strongly support the notion that a biased distribution of Lys and Arg residues between cytoplasmic and extra-cytoplasmic segments (the positive-inside rule) is present in most if not all organisms. © 2005 Wiley-Liss, Inc.

  • 45.
    Nordling, Erik
    et al.
    Dept. of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm.
    Kallberg, Yvonne
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Johansson, Jan
    Dept. of Anatomy, Physiology and Biochemistry Swedish University of Agricultural Sciences, Uppsala.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Molecular dynamics studies of x-helix stability in fibril-forming peptides2008In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 22, p. 53-58Article in journal (Refereed)
  • 46. Okamoto, H.
    et al.
    Hammarberg, T.
    Zhang, Y.-Y.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Watanabe, T.
    Samuelsson, B.
    Rådmark, O.
    Mutation analysis of the human 5-lipoxygenase C-terminus: Support for a stabilizing C-terminal loop2005In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1749, no 1, p. 123-131Article in journal (Refereed)
    Abstract [en]

    Lipoxygenases contain prosthetic iron, in human 5-lipoxygenase (5LO) the C-terminal isoleucine carboxylate constitutes one of five identified ligands. ATP is one of several factors determining 5LO activity. We compared properties of a series of 5LO C-terminal deletion mutants (one to six amino acid residues deleted). All mutants were enzymatically inactive (expected due to loss of iron), but expression yield (in E. coli) and affinity to ATP-agarose was markedly different. Deletion of up to four C-terminal residues was compatible with good expression and retained affinity to the ATP-column, as for wild-type 5LO. However when also the fifth residue was deleted (Asn-669) expression yield decreased and the affinity to ATP was markedly diminished. This was interpreted as a result of deranged structure and stability, due to loss of a hydrogen bond between Asn-669 and His-399. Mutagenesis of these residues supported this conclusion. In the structure of soybean lipoxygenase-1, a C-terminal loop was pointed out as important for correct orientation of the C-terminus. Accordingly, a hydrogen bond appears to stabilize such a C-terminal loop also in 5LO. © 2005 Elsevier B.V. All rights reserved.

  • 47.
    Ostberg, Linus J.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology. Karolinska Institute, Sweden .
    Stromberg, Patrik
    Karolinska Institute, Sweden .
    Hedberg, Jesper J.
    Karolinska Institute, Sweden .
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Hoog, Jan-Olov
    Karolinska Institute, Sweden .
    Analysis of mammalian alcohol dehydrogenase 5 (ADH5): Characterisation of rat ADH5 with comparisons to the corresponding human variant2013In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 202, no 1-3, p. 97-103Article in journal (Refereed)
    Abstract [en]

    Alcohol dehydrogenase 5 (ADH5) is a member of the mammalian alcohol dehydrogenase family of yet undefined functions. ADH5 was first identified at the DNA level in human and deer mouse. A rat alcohol dehydrogenase structure of similar type has been isolated at the cDNA level using human ADH5 as a screening probe, where the rat cDNA structure displayed several atypical properties. mRNA for rat ADH5 was found in multiple tissues, especially in the kidney. In vitro translation experiments indicated that rat ADH5 is expressed as efficiently as ADH1 and furthermore, rat ADH5 was readily expressed in COS cells fused to Green Fluorescent Protein. However, no soluble ADH5 protein could be heterologously expressed in Escherichia coil cells with expression systems successfully used for other mammalian ADHs, including fused to glutathione-S-transferase. Molecular modelling of the enzyme indicated that the protein does not fold in a productive way, which can be the explanation why no stable and active ADH5 has been isolated. These results indicate that ADH5, while readily expressed at the mRNA level, does not behave similarly to other mammalian ADHs investigated. The results, in vitro and in silico, suggest an unstable ADH5 structure, which can explain for why no active and stable protein can be isolated. Further possibilities are conceivable: the ADH5 protein may have to interact with a stabiliser, or the gene is actually a pseudogene.

  • 48.
    Persson, Bengt
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics.
    Bioinformatics in Membrane Protein Analysis2006In: Structural Genomics on Membrane Proteins / [ed] Lundstrom, Kenneth H., Boca Raton: Taylor&Francis Group , 2006, p. -400Chapter in book (Other academic)
    Abstract [en]

    While the genomic revolution has quickly led to the deposit of  more than 30,000 structures in the protein data bank (PDB), less than one percent of those contributions represent membrane proteins despite the fact that membrane proteins constitute some 20 percent of all proteins. This discrepancy becomes significantly troublesome when it is coupled with the fact that 60 percent of current drugs are based on targeting this group of proteins, a trend that does not seem likely to reverse.

    Structural Genomics on Membrane Proteinsprovides an excellent overview on novel research in bioinformatics and modeling on membranes, as well as the latest technological developments being employed in expression, purification, and crystallography to obtain high-resolution structures on membrane proteins. This cutting-edge work also explains the difficulties facing researchers—both technical and ethical—that have slowed the process. 

    Structural Genomics on Membrane Proteins provides researchers with an unprecedented look at the novel technologies that will ultimately allow them to conquer the last frontier in structural biology, leading to accelerated breakthroughs in drug discovery.

  • 49.
    Persson, Bengt
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Hedlund, Joel
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Jornvall, H
    Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    The MDR superfamily2008In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 65, no 24, p. 3879-3894Article in journal (Refereed)
    Abstract [en]

    The MDR superfamily with similar to 350-residue subunits contains the classical liver alcohol dehydrogenase (ADH), quinone reductase, leukotriene B4 dehydrogenase and many more forms. ADH is a dimeric zinc metalloprotein and occurs as five different classes in humans, resulting from gene duplications during vertebrate evolution, the first one traced to similar to 500 MYA (million years ago) from an ancestral formaldehyde dehydrogenase line. Like many duplications at that time, it correlates with enzymogenesis of new activities, contributing to conditions for emergence of vertebrate land life from osseous fish. The speed of changes correlates with function, as do differential evolutionary patterns in separate segments. Subsequent recognitions now define at least 40 human MDR members in the Uniprot database (corresponding to 25 genes when excluding close homologues), and in all species at least 10888 entries. Overall, variability is large, but like for many dehydrogenases, subdivided into constant and variable forms, corresponding to household and emerging enzyme activities, respectively. This review covers basic facts and describes eight large MDR families and nine smaller families. Combined, they have specific substrates in metabolic pathways, some with wide substrate specificity, and several with little known functions.

  • 50.
    Persson, Bengt
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics .
    Kallberg, Y.
    Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Oppermann, U.
    Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Jornvall, H.
    Jörnvall, H., Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs)2003In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 143-144, p. 271-278Conference paper (Other academic)
    Abstract [en]

    Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. In spite of a residue identity of only 15-30%, the folds are conserved to a large extent, with specific sequence motifs detectable. We have developed an assignment scheme based on these motifs and detect five families. Only two of these were known before, called 'Classical' and 'Extended', but are now distinguished at a further level based on patterns of charged residues in the coenzyme-binding region, giving seven subfamilies of classical SDRs and three subfamilies of extended SDRs. Three further families are novel entities, denoted 'Intermediate', 'Divergent' and 'Complex', encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, D. melanogaster, C. elegans, A. thaliana and S. cerevisiae. In the animal genomes, genes corresponding to the extended SDRs amount to around one quarter or less of the total number of SDR genes, while in those of A. thaliana and S. cerevisiae, the extended members constitute about 40% of the SDR forms. The NAD(H)-dependent SDRs are about equally many as the NADP(H)-dependent ones in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We also find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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