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  • 1.
    Alexandre, Campos
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Apraiz, Itzaso
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    da Fonseca, Rute R
    The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shotgun analysis of the marine mussel Mytilus edulis hemolymph proteome and mapping the innate immunity elements.2015In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 15, no 23-24, p. 4021-4029Article in journal (Refereed)
    Abstract [en]

    The marine mussel innate immunity provides protection to pathogen invasion and inflammation.In this regard, the mussel hemolymph takes a main role in the animal innate response.Despite the importance of this body fluid in determining the physiological condition of theanimal, little is known about the molecular mechanisms underlying the cellular and humoralresponses. In this work, we have applied aMS (nano-LC-MS/MS) strategy integrating genomicand transcriptomic data with the aim to: (i) identify the main protein functional groups thatcharacterize hemolymph and (ii) to map the elements of innate immunity in the marine musselMytilus edulis hemolymph proteome. After sample analysis and first protein identificationbased onMS/MS data comparison, proteins with unknown functions were annotated with blastusing public database (nrNCBI) information. Overall 595 hemolymph proteins were identifiedwith high confidence and annotated. These proteins encompass primary cellular metabolicprocesses: energy production and metabolism of biomolecules, as well as processes related tooxidative stress defence, xenobiotic detoxification, drug metabolism, and immune response.A group of proteins was identified with putative immune effector, receptor, and signalingfunctions in M. edulis. Data are available via ProteomeXchange with identifier PXD001951(http://proteomecentral.proteomexchange.org/dataset/PXD001951).

  • 2.
    Almeida, A. M.
    et al.
    CVZ Centre Vet and Zootecnia, Portugal; CIISA Centre Interdisciplinar Invest Sanidade Anim, Portugal; UNL, Portugal; IBET Institute Biol Expt and Tecnol, Portugal.
    Bassols, A.
    University of Autonoma Barcelona, Spain.
    Bendixen, E.
    Aarhus University, Denmark.
    Bhide, M.
    University of Vet Medical and Pharm, Slovakia.
    Ceciliani, F.
    University of Milan, Italy.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of Basque Country, Spain.
    Eckersall, P. D.
    University of Glasgow, Scotland.
    Hollung, K.
    Nofima AS, Norway.
    Lisacek, F.
    Swiss Institute Bioinformat, Switzerland.
    Mazzucchelli, G.
    University of Liege, Belgium.
    McLaughlin, M.
    University of Glasgow, Scotland.
    Miller, I.
    University of Vet Med, Austria.
    Nally, J. E.
    ARS, IA 50010 USA.
    Plowman, J.
    AgResearch, New Zealand.
    Renaut, J.
    Centre Rech Public Gabriel Lippmann, Luxembourg.
    Rodrigues, P.
    University of Algarve, Portugal.
    Roncada, P.
    University of Milan, Italy.
    Staric, J.
    University of Ljubljana, Slovenia.
    Turk, R.
    University of Zagreb, Croatia.
    Animal board invited review: advances in proteomics for animal and food sciences2015In: Animal, ISSN 1751-7311, E-ISSN 1751-732X, Vol. 9, no 1Article, review/survey (Refereed)
    Abstract [en]

    Animal production and health (APH) is an important sector in the world economy, representing a large proportion of the budget of all member states in the European Union and in other continents. APH is a highly competitive sector with a strong emphasis on innovation and, albeit with country to country variations, on scientific research. Proteomics (the study of all proteins present in a given tissue or fluid - i.e. the proteome) has an enormous potential when applied to APH. Nevertheless, for a variety of reasons and in contrast to disciplines such as plant sciences or human biomedicine, such potential is only now being tapped. To counter such limited usage, 6 years ago we created a consortium dedicated to the applications of Proteomics to APH, specifically in the form of a Cooperation in Science and Technology (COST) Action, termed FA1002 - Proteomics in Farm Animals: www.cost-faproteomics.org. In 4 years, the consortium quickly enlarged to a total of 31 countries in Europe, as well as Israel, Argentina, Australia and New Zealand. This article has a triple purpose. First, we aim to provide clear examples on the applications and benefits of the use of proteomics in all aspects related to APH. Second, we provide insights and possibilities on the new trends and objectives for APH proteomics applications and technologies for the years to come. Finally, we provide an overview and balance of the major activities and accomplishments of the COST Action on Farm Animal Proteomics. These include activities such as the organization of seminars, workshops and major scientific conferences, organization of summer schools, financing Short-Term Scientific Missions (STSMs) and the generation of scientific literature. Overall, the Action has attained all of the proposed objectives and has made considerable difference by putting proteomics on the global map for animal and veterinary researchers in general and by contributing significantly to reduce the East-West and North-South gaps existing in the European farm animal research. Future activities of significance in the field of scientific research, involving members of the action, as well as others, will likely be established in the future.

  • 3.
    Amelina, Hanna
    et al.
    Stockholm University.
    Sjodin, Marcus O. D.
    Uppsala University.
    Bergquist, Jonas
    Uppsala University.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Quantitative subproteomic analysis of age-related changes in mouse liver peroxisomes by iTRAQ LC-MS/MS2011In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 879, no 30, p. 3393-3400Article in journal (Refereed)
    Abstract [en]

    Aging is a complex multifactorial phenomenon, which is believed to result from the accumulation of cellular damage to biological macromolecules. Peroxisomes recently emerged as another important source of reactive oxygen species (ROS) production in addition to mitochondria. However, the role of these organelles in the process of aging is still not clear. The aim of this study was to characterize the changes in protein expression profiles of young (10 weeks old) versus old (18 months old) mouse liver peroxisome-enriched fractions. We have applied shotgun proteomic approach based on liquid chromatography and tandem mass spectrometry (LC-MS/MS) combined with iTRAQ (isobaric tags for relative and absolute quantitation) labeling that allows comparative quantitative multiplex analysis. Our analysis led to identification and quantification of 150 proteins, 8 out of which were differentially expressed between two age groups at a statistically significant level (p less than 0.05), with folds ranging from 1.2 to 4.1. These proteins involved in peroxisornal beta-oxidation, detoxification of xenobiotics and production of ROS. Noteworthy, differences in liver proteome have been observed between as well as within different age groups. In conclusion, our subproteomic quantitative study suggests that mouse liver proteome is sufficiently maintained until certain age.

  • 4.
    Bayat, N.
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sanchez-Dominguez, M.
    Centre Invest Mat Avanzados CIMAV SC, Mexico.
    Lakshmanan, R.
    Royal Institute Technology KTH, Sweden.
    Rajarao, G. K.
    Royal Institute Technology KTH, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Basque Country Medical Sch, Spain.
    Assessment of functionalized iron oxide nanoparticles in vitro: introduction to integrated nanoimpact index2015In: ENVIRONMENTAL SCIENCE-NANO, ISSN 2051-8153, Vol. 2, no 4, p. 380-394Article in journal (Refereed)
    Abstract [en]

    Functionalization of super paramagnetic iron oxide NPs (SPIONs) with different coatings renders them with unique physicochemical properties that allow them to be used in a broad range of applications such as drug targeting and water purification. However, it is required to fill the gap between the promises of any new functionalized SPIONs and the effects of these coatings on the NPs safety. Nanotoxicology is offering diverse strategies to assess the effect of exposure to SPIONs in a case-by-case manner but an integrated nanoimpact scale has not been developed yet. We have implemented the classical integrated biological response (IBR) into an integrated nanoimpact index (INI) as an early warning scale of nano-impact based on a combination of toxicological end points such as cell proliferation, oxidative stress, apoptosis and genotoxicity. Here, the effect of SPIONs functionalized with tri-sodium citrate (TSC), polyethylenimine (PEI), aminopropyl-triethoxysilane (APTES) and Chitosan (chitosan) were assessed on human keratinocytes and endothelial cells. Our results show that endothelial cells were more sensitive to exposure than keratinocytes and the initial cell culture density modulated the toxicity. PEI-SPIONs had the strongest effects in both cell types while TSC-SPIONS were the most biocompatible. This study emphasizes not only the importance of surface coatings but also the cell type and the initial cell density on the selection of toxicity assays. The INI developed here could offer an initial rationale to choose either modifying SPIONs properties to reduce its nanoimpact or performing a complete risk assessment to define the risk boundaries.

  • 5.
    Bayat, Narges
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schoelermann, Julia
    University of Bergen, Norway.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Stockholm University, Sweden; University of Basque Country, Spain.
    Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 63Article in journal (Refereed)
    Abstract [en]

    Ultra-small nanoparticles (USNPs) at 1-3 nm are a subset of nanoparticles (NPs) that exhibit intermediate physicochemical properties between molecular dispersions and larger NPs. Despite interest in their utilization in applications such as theranostics, limited data about their toxicity exist. Here the effect of TiO2-USNPs on endothelial cells in vitro, and zebrafish embryos in vivo, was studied and compared to larger TiO2-NPs (30 nm) and to single walled carbon nanotubes (SWCNTs). In vitro exposure showed that TiO2-USNPs were neither cytotoxic, nor had oxidative ability, nevertheless were genotoxic. In vivo experiment in early developing zebrafish embryos in water at high concentrations of TiO2-USNPs caused mortality possibly by acidifying the water and caused malformations in the form of pericardial edema when injected. Myo1C involved in glomerular development of zebrafish embryos was upregulated in embryos exposed to TiO2-USNPs. They also exhibited anti-angiogenic effects both in vitro and in vivo plus decreased nitric oxide concentration. The larger TiO2-NPs were genotoxic but not cytotoxic. SWCNTs were cytotoxic in vitro and had the highest oxidative ability. Neither of these NPs had significant effects in vivo. To our knowledge this is the first study evaluating the effects of TiO2-USNPs on vascular toxicity in vitro and in vivo and this strategy could unravel USNPs potential applications. (C) 2015 Elsevier Ltd. All rights reserved.

  • 6.
    Bayat, Narges
    et al.
    Stockholm University, Sweden .
    Rajapakse, Katarina
    University of Ljubljana, Slovenia .
    Marinsek-Logar, Romana
    University of Ljubljana, Slovenia .
    Drobne, Damjana
    University of Ljubljana, Slovenia Centre Excellence Adv Mat and Technology Future CONAMASTE, Slovenia Centre Excellence Nanosci and Nanotechnol CO Nanoctr, Slovenia .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The effects of engineered nanoparticles on the cellular structure and growth of Saccharomyces cerevisiae2014In: Nanotoxicology, ISSN 1743-5390, E-ISSN 1743-5404, Vol. 8, no 4, p. 363-373Article in journal (Refereed)
    Abstract [en]

    In order to study the effects of nanoparticles (NPs) with different physicochemical properties on cellular viability and structure, Saccharomyces cerevisiae were exposed to different concentrations of TiO2-NPs (1-3 nm), ZnO-NPs (less than100 nm), CuO-NPs (less than50 nm), their bulk forms, Ag-NPs (10 nm) and single-walled carbon nanotubes (SWCNTs). The GreenScreen assay was used to measure cyto- and genotoxicity, and transmission electron microscopy (TEM) used to assess ultrastructure. Cu-ONPs were highly cytotoxic, reducing the cell density by 80% at 9 cm(2)/ml, and inducing lipid droplet formation. Cells exposed to Ag-NPs (19 cm(2)/ml) and TiO2-NPs (147 cm(2)/ml) contained dark deposits in intracellular vacuoles, the cell wall and vesicles, and reduced cell density (40 and 30%, respectively). ZnO-NPs (8 cm(2)/ml) caused an increase in the size of intracellular vacuoles, despite not being cytotoxic. SWCNTs did not cause cytotoxicity or significant alterations in ultrastructure, despite high oxidative potential. Two genotoxicity assays, GreenScreen and the comet assay, produced different results and the authors discuss the reasons for this discrepancy. Classical assays of toxicity may not be the most suitable for studying the effects of NPs in cellular systems, and the simultaneous assessment of other measures of the state of cells, such as TEM are highly recommended.

  • 7.
    Bendz, Maria
    et al.
    Stockholm University, Sweden .
    Skwark, Marcin
    Stockholm University, Sweden .
    Nilsson, Daniel
    Stockholm University, Sweden .
    Granholm, Viktor
    Stockholm University, Sweden .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kall, Lukas
    Royal Institute Technology KTH, Sweden .
    Elofsson, Arne
    Stockholm University, Sweden .
    Membrane protein shaving with thermolysin can be used to evaluate topology predictors2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 9, p. 1467-1480Article in journal (Refereed)
    Abstract [en]

    Topology analysis of membrane proteins can be obtained by enzymatic shaving in combination with MS identification of peptides. Ideally, such analysis could provide quite detailed information about the membrane spanning regions. Here, we examine the ability of some shaving enzymes to provide large-scale analysis of membrane proteome topologies. To compare different shaving enzymes, we first analyzed the detected peptides from two over-expressed proteins. Second, we analyzed the peptides from non-over-expressed Escherichia coli membrane proteins with known structure to evaluate the shaving methods. Finally, the identified peptides were used to test the accuracy of a number of topology predictors. At the end we suggest that the usage of thermolysin, an enzyme working at the natural pH of the cell for membrane shaving, is superior because: (i) we detect a similar number of peptides and proteins using thermolysin and trypsin; (ii) thermolysin shaving can be run at a natural pH and (iii) the incubation time is quite short. (iv) Fewer detected peptides from thermolysin shaving originate from the transmembrane regions. Using thermolysin shaving we can also provide a clear separation between the best and the less accurate topology predictors, indicating that using data from shaving can provide valuable information when developing new topology predictors.

  • 8.
    Campos, Alexandre
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Danielsson, Gabriela
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.
    Farinha, Ana Paula
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Warholm, Per
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University.
    Shotgun proteomics to unravel marine mussel (Mytilus edulis) response to long-term exposure to low salinity and propranolol in a Baltic Sea microcosm2016In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 137, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Pharmaceuticals, among them the β-adrenoreceptor blocker propranolol, are an important group of environmental contaminants reported in European waters. Laboratory exposure to pharmaceuticals on marine species has been performed without considering the input of the ecosystem flow. To unravel the ecosystem response to long-term exposure to propranolol we have performed long-term exposure to propranolol and low salinity in microcosms. We applied shotgun proteomic analysis to gills of Mytilus edulis from those Baltic Sea microcosms and identified 2071 proteins with a proteogenomic strategy. The proteome profiling patterns from the 587 highly reproductive proteins among groups define salinity as a key factor in the mussel´s response to propranolol. Exposure at low salinity drives molecular mechanisms of adaptation based on a decrease in the abundance of several cytoskeletal proteins, signalling and intracellular membrane trafficking pathway combined with a response towards the maintenance of transcription and translation. The exposure to propranolol combined with low salinity modulates the expression of structural proteins including cilia functions and decrease the expression membrane protein transporters. This study reinforces the environment concerns of the impact of low salinity in combination with anthropogenic pollutants and anticipate critical physiological conditions for the survival of the blue mussel in the northern areas.

  • 9.
    Campos, Alexandre
    et al.
    University of Porto, Portugal .
    Tedesco, Sara
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Vasconcelos, Vitor
    University of Porto, Portugal University of Porto, Portugal .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Proteomic research in bivalves Towards the identification of molecular markers of aquatic pollution2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 14, p. 4346-4359Article, review/survey (Refereed)
    Abstract [en]

    Biomonitoring of aquatic environment and assessment of ecosystem health play essential roles in the development of effective strategies for the protection of the environment, human health and sustainable development. Biomarkers of pollution exposure have been extensively utilized in the last few decades to monitor the health of organisms and hence assess environmental status. However, the use of single biomarkers against biotic or abiotic stressors may be limited by the lack of sensitivity and specificity. Therefore, more recently, the search for novel biomarkers has been focused on the application of OMICS methodologies. Environmental proteomics focuses on the analysis of an organisms proteome and the detection of changes in the level of individual proteins/peptides in response to environmental stressors. Proteomics can provide a more robust approach for the assessment of environmental stress and therefore exposure to pollutants. This review aims to summarize the proteomic research in bivalves, a group of sessile and filter feeding organisms that play an important function as "sentinels" of the aquatic environment. A description of the main proteomic methodologies is provided. The current knowledge in bivalves toxicology, achieved with proteomics, is reported describing the main biochemical markers identified. A brief discussion regarding future challenges in this area of research emphasizing the development of more descriptive gene/protein databases that could support the OMICs approaches is presented. less thanbrgreater than less thanbrgreater thanThis article is part of a Special Issue entitled: Farm animal proteomics.

  • 10.
    Cristobal, Susana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Amelina, H
    Stockholm University.
    Apraiz, I
    Stockholm University.
    Bayat, N
    Stockholm University.
    Danielsson, G
    Stockholm University.
    Environmental proteomics in pollution assessment in INTEGRATIVE AND COMPARATIVE BIOLOGY, vol 52, issue , pp E38-E382012In: INTEGRATIVE AND COMPARATIVE BIOLOGY, Oxford University Press (OUP): Policy B , 2012, Vol. 52, p. E38-E38Conference paper (Refereed)
    Abstract [en]

    n/a

  • 11.
    Cristobal, Susana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tedesco, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bayat, Narges
    Stockholm University.
    Danielsson, Gabriela
    Stockholm University.
    Buque, Xavier
    Basque country University, Spain.
    Aspichueta, Patricia
    Basque Country University, Spain.
    Fresnedo, Olatz
    Basque Country University, Spain.
    Proteomic and lipidomic analysis of primary mouse hepatocytes exposed to metal and metal oxide nanoparticles2015In: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 5, no 1, p. 44-57Article in journal (Refereed)
    Abstract [en]

    The global analysis of the cellular lipid and protein content upon exposure to metal and metal oxide nanoparticles (NPs) can provide an overviewof the possible impact of exposure. Proteomic analysis has been applied to understand the nanoimpact however the relevance of the alterationon the lipidic proOle has been underestimated. In our study, primary mouse hepatocytes were treated with ultra-small (US) TiO2-USNPsas well as ZnO-NPs, CuO-NPs and Ag-NPs. e protein extracts were analysed by 2D-DIGE and quantiOed by imaging soPware and the selecteddi9erentially expressed proteins were identiOed by nLC-ESI-MS/MS. In parallel, lipidomic analysis of the samples was performed usingthin layer chromatography (TLC) and analyzed by imaging soPware. Our Ondings show an overall ranking of the nanoimpact at the cellularand molecular level: TiO2-USNPs<ZnO-NPs<Ag-NPs<CuO-NPs. CuO-NPs and Ag-NPs were cytotoxic while ZnO-NPs and CuO-NPs hadoxidative capacity. TiO2-USNPs did not have oxidative capacity and were not cytotoxic. e most common cellular impact of the exposurewas the down-regulation of proteins. e proteins identiOed were involved in urea cycle, lipid metabolism, electron transport chain, metabolismsignaling, cellular structure and we could also identify nuclear proteins. CuO-NPs exposure decreased phosphatidylethanolamine andphosphatidylinositol and caused down-regulation of electron transferring protein subunit beta. Ag-NPs exposure caused increased of totallipids and triacylglycerol and decrease of sphingomyelin. TiO2-USNPs also caused decrease of sphingomyelin as well as up-regulation of ATPsynthase and electron transferring protein alfa. ZnO-NPs a9ected the proteome in a concentration-independent manner with down-regulationof RNA helicase. ZnO-NPs exposure did not a9ect the cellular lipids. To our knowledge this work represents the Orst integrated proteomic andlipidomic approach to study the e9ect of NPs exposure to primary mouse hepatocytes in vitro.

  • 12.
    Fleenor, Courtney J.
    et al.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Globeimmune Inc, CO USA.
    Arends, Tessa
    Univ Colorado, CO 80045 USA.
    Lei, Hong
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Okuyama, Kazuki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rabe, Jennifer L.
    Univ Colorado, CO 80045 USA.
    Pandey, Ahwan
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Danhorn, Thomas
    Natl Jewish Hlth, CO USA.
    Straign, Desiree
    Natl Jewish Hlth, CO 80206 USA.
    Espinosa, Joaquin M.
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Warming, Soren
    Genentech Inc, CA 94080 USA.
    Pietras, Eric M.
    Univ Colorado, CO USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hagman, James R.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Univ Colorado, CO 80045 USA.
    Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment2018In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 38, no 17, article id UNSP e00603-17Article in journal (Refereed)
    Abstract [en]

    Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Kruppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated Zfp521 genes (Zfp521(-/-)) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes bone marrow microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.

    The full text will be freely available from 2018-12-18 14:43
  • 13.
    Garcia-Sanchez, Susana
    et al.
    University of Basque Country UPV EHU, Spain.
    Bernales, Irantzu
    University of Basque Country UPV EHU, Spain.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of Basque Country UPV EHU, Spain.
    Early response to nanoparticles in the Arabidopsis transcriptome compromises plant defence and root-hair development through salicylic acid signalling2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, no 341Article in journal (Refereed)
    Abstract [en]

    Background: The impact of nano-scaled materials on photosynthetic organisms needs to be evaluated. Plants represent the largest interface between the environment and biosphere, so understanding how nanoparticles affect them is especially relevant for environmental assessments. Nanotoxicology studies in plants allude to quantum size effects and other properties specific of the nano-stage to explain increased toxicity respect to bulk compounds. However, gene expression profiles after exposure to nanoparticles and other sources of environmental stress have not been compared and the impact on plant defence has not been analysed. Results: Arabidopsis plants were exposed to TiO2-nanoparticles, Ag-nanoparticles, and multi-walled carbon nanotubes as well as different sources of biotic (microbial pathogens) or abiotic (saline, drought, or wounding) stresses. Changes in gene expression profiles and plant phenotypic responses were evaluated. Transcriptome analysis shows similarity of expression patterns for all plants exposed to nanoparticles and a low impact on gene expression compared to other stress inducers. Nanoparticle exposure repressed transcriptional responses to microbial pathogens, resulting in increased bacterial colonization during an experimental infection. Inhibition of root hair development and transcriptional patterns characteristic of phosphate starvation response were also observed. The exogenous addition of salicylic acid prevented some nano-specific transcriptional and phenotypic effects, including the reduction in root hair formation and the colonization of distal leaves by bacteria. Conclusions: This study integrates the effect of nanoparticles on gene expression with plant responses to major sources of environmental stress and paves the way to remediate the impact of these potentially damaging compounds through hormonal priming.

  • 14.
    Ge, Yue
    et al.
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Wang, Da-Zhi
    State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, China .
    Chiu, Jen-Fu
    University of Hong Kong and Shantou University College of Medicine, China.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sheehan, David
    Department of Biochemistry, University College Cork, Ireland.
    Silvestre, Frédéric
    Research Unit in Environmental and Evolutionary Biology, University of Namur, Belgium.
    Peng, Xianxuan
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Li, Hui
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Gong, Zhiyuan
    Department of Biological Sciences, National University of Singapore, Singapore.
    Lam, Siew Hong
    Department of Biological Sciences, National University of Singapore, Singapore.
    Wentao, Hu
    Department of Biochemistry, University College Cork, Ireland.
    Iwahashi, Hitoshi
    Department of Applied Biological Sciences, Gifu University, Japan.
    Liu, Jianjun
    Shenzhen Center for Disease Control and Prevention, China.
    Mei, Nan
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Shi, Leming
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Bruno, Maribel
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Foth, Heidi
    Institute for Environmental Toxicology, Martin Luther University, Halle/Saale, Germany.
    Teichman, Kevin
    Office of Research and Development, U.S. Environmental Protection Agency, Washington D.C., USA.
    Environmental OMICS: Current Status and Future Directions2013In: JOURNAL OF INTEGRATED OMICS, ISSN 2182-0287, Vol. 3, no 2, p. 75-87Article in journal (Refereed)
    Abstract [en]

    Applications of OMICS to high throughput studies of changes of genes, RNAs, proteins, metabolites, and their associated functionsin cells or organisms exposed to environmental chemicals has led to the emergence of a very active research field: environmental OMICS.This developing field holds an important key for improving the scientific basis for understanding the potential impacts of environmentalchemicals on both health and the environment. Here we describe the state of environmental OMICS with an emphasis on its recent accomplishmentsand its problems and potential solutions to facilitate the incorporation of OMICS into mainstream environmental and healthresearch.Data sources: We reviewed relevant and recently published studies on the applicability and usefulness of OMICS technologies to the identificationof toxicity pathways, mechanisms, and biomarkers of environmental chemicals for environmental and health risk monitoring andassessment, including recent presentations and discussions on these issues at The First International Conference on Environmental OMICS(ICEO), held in Guangzhou, China during November 8-12, 2011. This paper summarizes our review.Synthesis: Environmental OMICS aims to take advantage of powerful genomics, transcriptomics, proteomics, and metabolomics tools toidentify novel toxicity pathways/signatures/biomarkers so as to better understand toxicity mechanisms/modes of action, to identify/categorize/prioritize/screen environmental chemicals, and to monitor and predict the risks associated with exposure to environmental chemicalson human health and the environment. To improve the field, some lessons learned from previous studies need to be summarized, aresearch agenda and guidelines for future studies need to be established, and a focus for the field needs to be developed.Conclusions: OMICS technologies for identification of RNA, protein, and metabolic profiles and endpoints have already significantly improvedour understanding of how environmental chemicals affect our ecosystem and human health. OMICS breakthroughs are empoweringthe fields of environmental toxicology, chemical toxicity characterization, and health risk assessment. However, environmental OMICS is stillin the data generation and collection stage. Important data gaps in linking and/or integrating toxicity data with OMICS endpoints/profilesneed to be filled to enable understanding of the potential impacts of chemicals on human health and the environment. It is expected thatfuture environmental OMICS will focus more on real environmental issues and challenges such as the characterization of chemical mixturetoxicity, the identification of environmental and health biomarkers, and the development of innovative environmental OMICS approachesand assays. These innovative approaches and assays will inform chemical toxicity testing and prediction, ecological and health risk monitoringand assessment, and natural resource utilization in ways that maintain human health and protects the environment in a sustainable manner.

  • 15.
    Helander, Sara
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Montecchio, Meri
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pilstål, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Su, Yulong
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Johansson, Malin
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Sweden.
    Mohammed, Javed
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sears, Rosalie
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Department of Social and Welfare Studies, Learning, Aesthetics, Natural science. Linköping University, Faculty of Educational Sciences. Linköping University, Faculty of Science & Engineering.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity2015In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, p. 2267-2279Article in journal (Refereed)
    Abstract [en]

    Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

  • 16.
    Kuruvilla, Jacob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Farinha, Ana Paula
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bayat, Narges
    Department of Biochemistry and Biophysics, Arrhenius laboratories, Stockholm University, Stockholm, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. IKERBASQUE, Basque Foundation for Science, Department of Physiology, Faculty of Medicine and Dentristy, University of the Basque Country, Leioa, Spain.
    Surface proteomics on nanoparticles, a step to simplify the rapid prototyping of nanoparticles2017In: Nanoscale Horizons, ISSN 2055-6756, no 1, p. 55-64Article in journal (Refereed)
    Abstract [en]

    Engineered nanoparticles for biomedical applications requireincreasing effectiveness in targeting specific cells while preservingnon-target cell’s safety. We developed a surface proteomicsmethod for a rapid and systematic analysis of the interphasebetween the nanoparticle protein corona and the targeting cellsthat could implement the rapid prototyping of nanomedicines.Native nanoparticles entering in a protein-rich liquid mediaquickly form a macromolecular structure called protein corona.This protein structure defines the physical interaction betweennanoparticles and target cells. The surface proteins compose thefirst line of interaction between this macromolecular structureand the cell surface of a target cell. We demonstrated that SUSTU(SUrface proteomics, Safety, Targeting, Uptake) provides aqualitative and quantitative analysis from the protein coronasurface. With SUSTU, the spatial dynamics of the protein coronasurface can be studied. Data from SUSTU would ascertain thenanoparticle functionalized groups exposed at destiny that couldcircumvent preliminary in vitro experiments. Therefore thismethod could implement the analysis of nanoparticle targetingand uptake capability and could be integrated into a rapidprototyping strategy which is a major challenge in nanomaterialscience. Data are available via ProteomeXchange with identifierPXD004636.

  • 17.
    Lopes, Viviana R
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Audinot, Jean‑Nicolas
    Luxembourg Institute of Science and Technology, Luxembourg.
    Bayat, Narges
    Stockholm University, Sweden.
    Gutleb, Arno C.
    Luxembourg Institute of Science and Technology, Luxembourg.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dose‑dependent autophagic effectof titanium dioxide nanoparticles in humanHaCaT cells at non‑cytotoxic levels2016In: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 14, no 22, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Background: Interactions between nanoparticles and cells are now the focus of a fast-growing area of research.Though many nanoparticles interact with cells without any acute toxic responses, metal oxide nanoparticles includingthose composed of titanium dioxide (TiO2-NPs) may disrupt the intracellular process of macroautophagy.Autophagy plays a key role in human health and disease, particularly in cancer and neurodegenerative diseases. Weherein investigated the in vitro biological effects of TiO2-NPs (18 nm) on autophagy in human keratinocytes (HaCaT)cells at non-cytotoxic levels.Results: TiO2-NPs were characterized by transmission electron microscopy (TEM) and dynamic light scatteringtechniques. Cellular uptake, as evaluated by TEM and NanoSIMS revealed that NPs internalization led to the formationof autophagosomes. TiO2-NPs treatment did not reduce cell viability of HaCaT cells nor increased oxidative stress. Cellularautophagy was additionally evaluated by confocal microscopy using eGFP-LC3 keratinocytes, western blottingof autophagy marker LC3I/II, immunodetection of p62 and NBR1 proteins, and gene expression of LC3II, p62, NBR1,beclin1 and ATG5 by RT-qPCR. We also confirmed the formation and accumulation of autophagosomes in NPs treatedcells with LC3-II upregulation. Based on the lack of degradation of p62 and NBR1 proteins, autophagosomes accumulationat a high dose (25.0 μg/ml) is due to blockage while a low dose (0.16 μg/ml) promoted autophagy. Cellularviability was not affected in either case.Conclusions: The uptake of TiO2-NPs led to a dose-dependent increase in autophagic effect under non-cytotoxicconditions. Our results suggest dose-dependent autophagic effect over time as a cellular response to TiO2-NPs. Mostimportantly, these findings suggest that simple toxicity data are not enough to understand the full impact of TiO2-NPsand their effects on cellular pathways or function.

  • 18.
    Marco-Ramell, Anna
    et al.
    Universitat Autònoma de Barcelona, Spain; Univ Barcelona, Spain.
    de Almeida, Andree M
    Instituto de Biologia Experimental e Tecnologica, Oeiras, Portugal; Univ Lisbon, Fac, Lisbon, Portugal; Ross Univ, Sch Vet Med, Basseterre, St Kitts & Nevi.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Leioa, Spain.
    Rodrigues, Pedro
    University of Algarve, Portugal.
    Roncada, Paola
    Istituto Sperimentale Italiano L. Spallanzani, Milano, Italy.
    Bassols, Anna
    Universitat Autònoma de Barcelona, Spain.
    Proteomics and the search for welfare and stress biomarkers in animal production in the one health context2016In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 7, p. 2024-2035Article, review/survey (Refereed)
    Abstract [en]

    Stress and welfare are important factors to animal production in a context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define markers for stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of varied stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how Proteomics and Systems Biology are key elements to the study of stress and welfare on farm animals and a powerful tool to animal welfare, health and productivity.

  • 19.
    Rajapakse, K.
    et al.
    University of Ljubljana, Ljubljana, Slovenia.
    Drobne, D.
    University of Ljubljana, Ljubljana, Slovenia.
    Kastelec, D.
    University of Ljubljana, Ljubljana, Slovenia.
    Kogej, K.
    University of Ljubljana, Ljubljana, Slovenia.
    Makovec, D.
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Gallampois, Christine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Amelina, H.
    Stockholm University, Stockholm, Sweden.
    Danielsson, G.
    Stockholm University, Stockholm, Sweden.
    Fanedl, L.
    University of Ljubljana, Ljubljana, Slovenia.
    Marinsek-Logar, R.
    University of Ljubljana, Ljubljana, Slovenia.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. IKERBASQUE, Basque Foundation for Science, University of the Basque Country, Leioa, Spain.
    Proteomic analyses of early response of unicellular eukaryotic microorganism Tetrahymena thermophila exposed to TiO2 particles.2016In: Nanotoxicology, ISSN 1743-5390, E-ISSN 1743-5404, Vol. 10, no 5, p. 542-556Article in journal (Refereed)
    Abstract [en]

    Key biological functions involved in cell survival have been studied to understand the difference between the impact of exposure to TiO2 nanoparticles (TiO2-NPs) and their bulk counterparts (bulk-TiO2). By selecting a unicellular eukaryotic model organism and applying proteomic analysis an overview of the possible impact of exposure could be obtained. In this study, we investigated the early response of unicellular eukaryotic protozoan Tetrahymena thermophila exposed to TiO2-NPs or bulk-TiO2 particles at subtoxic concentrations for this organism. The proteomic analysis based on 2DE + nLC-ESI-MS/MS revealed 930 distinct protein spots, among which 77 were differentially expressed and 18 were unambiguously identified. We identified alterations in metabolic pathways, including lipid and fatty acid metabolism, purine metabolism and energetic metabolism, as well as salt stress and protein degradation. This proteomic study is consistent with our previous findings, where the early response of T. thermophila to subtoxic concentrations of TiO2 particles included alterations in lipid and fatty acid metabolism and ion regulation. The response to the lowest TiO2-NPs concentration differed significantly from the response to higher TiO2-NPs concentration and both bulk-TiO2concentrations. Alterations on the physiological landscape were significant after exposure to both nano- and bulk-TiO2; however, no toxic effects were evidenced even at very high exposure concentrations. This study confirms the relevance of the alteration of the lipid profile and lipid metabolism in understanding the early impact of TiO2-NPs in eukaryotic cells, for example, phagocytosing cells like macrophages and ciliated cells in the respiratory epithelium.

  • 20.
    Tedesco, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mullen, William
    University of Glasgow, Scotland .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Univ Basque Country, Spain .
    High-Throughput Proteomics: A New Tool for Quality and Safety in Fishery Products2014In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 15, no 2, p. 118-133Article, review/survey (Refereed)
    Abstract [en]

    In order to cope with the increasing demand for fishery products, sensitive technological tools are required to ensure high quality and wholesomeness and to monitor their production process in a sustainable manner while complying with the strict standards imposed by regulatory authorities. Proteomics may assist the industry as it allows an unbiased approach in the discovery of biomarkers that could be used to increase our understanding of different biological, physiological and ecological aspects that may be advantageous in optimizing quality and safety in aquatic species. The aim of this review is to highlight the potential of cost-effective high-throughput technologies, such as those offered by proteomics using "on-line" mass spectrometry to improve the efficiency of the industry in identifying biomarkers relevant for safe high quality products.

  • 21.
    Virkki, Minttu T.
    et al.
    Stockholm University, Solna, Sweden.
    Agrawal, Nitin
    Åbo Akademi, Turku, Finland.
    Edsbacker, Elin
    Stockholm University, Solna, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of the Basque Country, Leioa, Spain.
    Elofsson, Arne
    Stockholm University, Solna, Sweden.
    Kauko, Anni
    Åbo Akademi, Turku, Finland.
    Folding of Aquaporin 1: multiple evidence that helix 3 can shift out of the membrane core2014In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 23, no 7, p. 981-992Article in journal (Refereed)
    Abstract [en]

    The folding of most integral membrane proteins follows a two-step process: initially, individual transmembrane helices are inserted into the membrane by the Sec translocon. Thereafter, these helices fold to shape the final conformation of the protein. However, for some proteins, including Aquaporin 1 (AQP1), the folding appears to follow a more complicated path. AQP1 has been reported to first insert as a four-helical intermediate, where helix 2 and 4 are not inserted into the membrane. In a second step, this intermediate is folded into a six-helical topology. During this process, the orientation of the third helix is inverted. Here, we propose a mechanism for how this reorientation could be initiated: first, helix 3 slides out from the membrane core resulting in that the preceding loop enters the membrane. The final conformation could then be formed as helix 2, 3, and 4 are inserted into the membrane and the reentrant regions come together. We find support for the first step in this process by showing that the loop preceding helix 3 can insert into the membrane. Further, hydrophobicity curves, experimentally measured insertion efficiencies and MD-simulations suggest that the barrier between these two hydrophobic regions is relatively low, supporting the idea that helix 3 can slide out of the membrane core, initiating the rearrangement process.

  • 22.
    Virkki, Minttu T.
    et al.
    Stockholm University, Sweden .
    Peters, Christoph
    Stockholm University, Sweden; Swedish e-Science Research Center (SeRC), Stockholm, Sweden.
    Nilsson, Daniel
    Stockholm University, Sweden .
    Sörensen, Therese
    Stockholm University, Sweden .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of the Basque Country, Leioa, Spain.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Elofsson, Arne
    Stockholm University, Sweden; Swedish E Science Research Centre SeRC, Stockholm, Sweden .
    The Positive Inside Rule Is Stronger When Followed by a Transmembrane Helix2014In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 426, no 16, p. 2982-2991Article in journal (Refereed)
    Abstract [en]

    The translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs, these arginines do not aid in the recognition without the rest of the subsequent helix; that is, the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows: the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted; that is, the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism obviously cannot aid C-terminal helices, and consequently, we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices.

1 - 22 of 22
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