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  • 1.
    A. Strumpfer, Johan
    et al.
    University of Illinois at Urbana Champaign, Urbana, IL, USA; Beckman Institute, Urbana, IL, USA.
    von Castelmur, Eleonore
    Institute of Integrative Biology, University of Liverpool, Liverpool, IL, USA.
    Franke, Barbara
    Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
    Barbieri, Sonia
    Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
    Bogomolovas, Julijus
    Universitätsmedizin Mannheim, Mannheim, Germany.
    Qadota, Hiroshi
    Department of Pathology, Emory University, Atlanta, GA, USA.
    Konarv, Petr
    European Molecular Biology Laboratory, Hamburg, Germany.
    Svergun, Dmitri
    European Molecular Biology Laboratory, Hamburg, Germany.
    Labeit, Siegfried
    Department for Integrative Pathophysiology, Universitätsmedizin Mannheim, Mannheim, Germany.
    Schulten, Klaus
    University of Illinois at Urbana Champaign, Urbana, IL, USA Beckman Institute, Urbana, IL, USA.
    Benian, Guy
    Department of Pathology, Emory University, Atlanta, GA, USA.
    Mayans, Olga
    Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
    Stretching of Twitchin Kinase2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3 Supplement 1, p. 361a-362aArticle in journal (Refereed)
    Abstract [en]

    The giant proteins from the titin family, that form cytoskeletal filaments, have emerged as key mechanotransducers in the sarcomere. These proteins contain a conserved kinase region, which is auto-inhibited by a C-terminal tail domain. The inhibitory tail domain occludes the active sites of the kinases, thus preventing ATP from binding. It was proposed that through application of a force, such as that arising during muscle contraction, the inhibitory tail becomes detached, lifting inhibition. The force-sensing ability of titin kinase was demonstrated in AFM experiments and simulations [Puchner, et al., 2008, PNAS:105, 13385], which showed indeed that mechanical forces can remove the autoinhibitory tail of titin kinase. We report here steered molecular dynamics simulations (SMD) of the very recently resolved crystal structure of twitchin kinase, containing the kinase region and flanking fibronectin and immuniglobulin domains, that show a variant mechanism. Despite the significant structural and sequence similarity to titin kinase, the autoinhibitory tail of twitchin kinase remains in place upon stretching, while the N-terminal lobe of the kinase unfolds. The SMD simulations also show that the detachment and stretching of the linker between fibronectin and kinase regions, and the partial extension of the autoinhibitory tail, are the primary force-response. We postulate that this stretched state, where all structural elements are still intact, may represent the physiologically active state.

  • 2.
    Akanda, Nesar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, no 12, p. 4405-4417Article in journal (Refereed)
    Abstract [en]

    Ion channels in the plasma membrane play critical roles in apoptosis. In a recent study we found that a voltage-dependent anion channel in the plasma membrane (VDACpl) of neuronal hippocampal cell line (HT22) cells was activated during apoptosis and that channel block prevented apoptosis. Whether or not VDACpl is identical to the mitochondrial VDACmt has been debated. Here, we biophysically characterize the apoptosis-inducing VDACpl and compare it with other reports of VDACpls and VDACmt. Excised membrane patches of apoptotic HT22 cells were studied with the patch-clamp technique. VDACpl has a large main-conductance state (400 pS) and occasionally subconductance states of µ28 pS and 220 pS. The small subconductance state is associated with long-lived inactivated states, and the large subconductance state is associated with excision of the membrane patch and subsequent activation of the channel. The open-probability curve is bell shaped with its peak around 0mV and is blocked by 30µM Gd3+. The gating can be described by a symmetrical seven-state model with one open state and six closed or inactivated states. These channel properties are similar to those of VDACmt and other VDACpls and are discussed in relation to apoptosis.

  • 3. Alam, MT
    et al.
    Yamada, T
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Ikai, A
    The importance of being knotted: Effects of the C-terminal knot structure on enzymatic and mechanical properties of bovine carbonic anhydrase II2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 2, p. 159A-159AConference paper (Other academic)
  • 4.
    Boström, Mathias
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics .
    Williams, DRM
    Ninham, BW
    Special ion effects: Why the properties of lysozyme in salt solutions follow a Hofmeister series2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 85, no 2, p. 686-694Article in journal (Refereed)
    Abstract [en]

    Protein solubility in aqueous solutions depends in a complicated and not well understood way on pH, salt type, and salt concentration. Why for instance does the use of two different monovalent salts, potassium thiocyanate and potassium chloride, produce such different results? One important and previously neglected source of ion specificity is the ionic dispersion potential that acts between each ion and the protein. This attractive potential is found to be much stronger for SCN- than it is for Cl-. We present model calculations, performed within a modified ion-specific double-layer theory, that demonstrate the large effect of including these ionic dispersion potentials. The results are consistent with experiments performed on hen egg-white lysozymes and on neutral black lipid membranes. The calculated surface pH and net lysozyme charge depend strongly on the choice of anion. We demonstrate that the lysozyme net charge is larger, and the corresponding Debye length shorter, in a thiocyanate salt solution than in a chloride salt solution. Recent experiments have suggested that pK(a) values of histidines depend on salt concentration and on ionic species. We finally demonstrate that once ionic dispersion potentials are included in the theory these results can quantitatively be reinterpreted in terms of a highly specific surface pH (and a salt-independent pK(a)).

  • 5.
    Brorsson, Ann-Christin
    et al.
    University of Cambridge.
    Bolognesi, Benedetta
    University of Cambridge.
    Tartaglia, Gian Gaetano
    University of Cambridge.
    Shammas, Sarah L
    University of Cambridge.
    Favrin, Giorgio
    University of Cambridge.
    Watson, Ian
    University of Cambridge.
    Lomas, David A
    University of Cambridge.
    Chiti, Fabrizio
    Università degli Studi di Firenze, Italy.
    Vendruscolo, Michele
    University of Cambridge.
    Dobson, Christopher M
    University of Cambridge.
    Crowther, Damian C
    University of Cambridge.
    Luheshi, Leila M
    University of Cambridge.
    Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 8, p. 1677-84Article in journal (Refereed)
    Abstract [en]

    The extent to which proteins aggregate into distinct structures ranging from prefibrillar oligomers to amyloid fibrils is key to the pathogenesis of many age-related degenerative diseases. We describe here for the Alzheimer's disease-related amyloid beta peptide (Abeta) an investigation of the sequence-based determinants of the balance between the formation of prefibrillar aggregates and amyloid fibrils. We show that by introducing single-point mutations, it is possible to convert the normally harmless Abeta40 peptide into a pathogenic species by increasing its relative propensity to form prefibrillar but not fibrillar aggregates, and, conversely, to abolish the pathogenicity of the highly neurotoxic E22G Abeta42 peptide by reducing its relative propensity to form prefibrillar species rather than mature fibrillar ones. This observation can be rationalized by the demonstration that whereas regions of the sequence of high aggregation propensity dominate the overall tendency to aggregate, regions with low intrinsic aggregation propensities exert significant control over the balance of the prefibrillar and fibrillar species formed, and therefore play a major role in determining the neurotoxicity of the Abeta peptide.

  • 6.
    Börjesson, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids2008In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 5, p. 2242-2253Article in journal (Refereed)
    Abstract [en]

    Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that ω-3 and ω-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology. © 2008 by the Biophysical Society.

  • 7.
    Börjesson, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Parkkari, Teija
    University of Kuopio, Finland.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Electrostatic Tuning of Cellular Excitability2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 396-403Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channels voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachiclonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.

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  • 8.
    Caporaletti, Francesca
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Large Scale Structure, Institute Laue Langevin, Grenoble, France.
    Pietras, Zuzanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Morad, Vivian
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Gabel, Frank
    University Grenoble Alpes, CEA, CNRS, IBS, Grenoble, France.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Martel, Anne
    Large Scale Structure, Institute Laue Langevin, Grenoble, France.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Small-angle X-ray and neutron scattering of MexR and its complex with DNA supports a conformational selection binding model.2023In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 122, no 2, p. 408-418Article in journal (Refereed)
    Abstract [en]

    In this work, we used Small-angle X-ray and neutron scattering (SAS) to reveal the shape of the protein-DNA complex of the Pseudomonas aeruginosa (P.aeruginosa) transcriptional regulator MexR, a member of the MarR family, when bound to one of its native DNA binding sites. Several MarR-like proteins, including MexR, repress the expression of efflux pump proteins by binding to DNA on regulatory sites overlapping with promoter regions. When expressed, efflux-proteins self-assemble to form multiprotein complexes and actively expel highly toxic compounds out of the host organism. The mutational pressure on efflux-regulating MarR family proteins is high since deficient DNA binding leads to constitutive expression of efflux pumps and thereby supports acquired multidrug resistance. Understanding the functional outcome of such mutations and their effects on DNA binding has been hampered by the scarcity of structural and dynamic characterisation of both free and DNA-bound MarR proteins. Here, we show how combined neutron and X-ray small-angle scattering (SAS) of both states in solution support a conformational selection model that enhances MexR asymmetry in binding to one of its promoter-overlapping DNA binding sites.

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  • 9.
    Carlsson, Uno
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Lindgren, M
    Persson, M
    Freskgård, Per-Ola
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Mårtensson, Lars-Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Andersson, D
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Svensson, Magdalena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Aggregation is site-specific in carbonic anhydrase and is prevented by GroEL: The interaction leads to a more flexible structure of both the protein substrate and the chaperonin.2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 202Pos-Conference paper (Other academic)
  • 10.
    Elinder, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Madeja, Michael
    University of Munster, Germany; Goethe University of Frankfurt, Germany.
    Zeberg, Hugo
    Karolinska Institute, Sweden.
    Arhem, Peter
    Karolinska Institute, Sweden.
    Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.12016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 8, p. 1679-1691Article in journal (Refereed)
    Abstract [en]

    The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr2+) on the voltage dependence of the G(V) curves of wild-type and chimeric Kv channels expressed in Xenopus oocytes, using the voltage-clamp technique. Out of seven Kv channels, Kv1.2 was found to be most sensitive to Sr2+ (50 mM shifted G(V) by +21.7 mV), and Kv2.1 to be the least sensitive (+7.8 mV). Experiments on 25 chimeras, constructed from Kv1.2 and Kv2.1, showed that the large Sr2+-induced G(V) shift of Kv1.2 can be transferred to Kv2.1 by exchanging the extracellular linker between S3 and S4 (L3/4) in combination with either the extracellular linker between S5 and the pore (L5/P) or that between the pore and S6 (LP/6). The effects of the linker substitutions were nonadditive, suggesting specific structural interactions. The free energy of these interactions was similar to 20 kJ/mol, suggesting involvement of hydrophobic interactions and/or hydrogen bonds. Using principles from double-layer theory we derived an approximate linear equation (relating the voltage shifts to altered ionic strength), which proved to well match experimental data, suggesting that Sr2+ acts on these channels mainly by screening surface charges. Taken together, these results highlight the extracellular surface potential at the voltage sensor as an important determinant of the channels voltage dependence, making the extracellular linkers essential targets for evolutionary selection.

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  • 11.
    Elinder, Fredrik
    et al.
    Karolinska Institute.
    Århem, P
    Karolinska Institute.
    Role of individual surface charges of voltage-gated K channels1999In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 77, no 3, p. 1358-1362Article in journal (Refereed)
    Abstract [en]

    Fixed charges on the extracellular surface of voltage-gated ion channels influence the gating. In previous studies of cloned voltage-gated K channels, we found evidence that the functional surface charges are located on the peptide loop between the fifth transmembrane segment and the pore region (the S5-P loop). In the present study, we determine the role of individual charges of the S5-P loop by correlating primary structure with experimentally calculated surface potentials of the previously investigated channels. The results suggest that contributions to the surface potential at the voltage sensor of the different residues varies in an oscillating pattern, with the first residue of the N-terminal end of the S5-P loop, an absolutely conserved glutamate, contributing most. An analysis yields estimates of the distance between the residues and the voltage sensor, the first N-terminal residue being located at a distance of 5-6 Angstrom. To explain the results, a structural hypothesis, comprising an a-helical N-terminal end of the S5-P loop, is presented.

  • 12.
    Franco-Gonzalez, Juan F.
    et al.
    BIOPHYM, IEM, CSIC, Madrid, Spain.
    Cruz, Victor
    BIOPHYM, IEM, CSIC, Madrid, Spain.
    Ramos, Javier
    BIOPHYM, IEM, CSIC, Madrid, Spain.
    Martinez-Salazar, Javier
    BIOPHYM, IEM, CSIC, Madrid, Spain.
    Protein-Protein and Protein-Membrane Interactions Regarding the Erbb2/Trastuzumab-Fab Complexes. A Coarse-Grained Molecular Dynamics Description2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 666-667Article in journal (Refereed)
    Abstract [en]

    ErbB2 is a member of epidermal growth factor receptor (EGFR) family and is overexpressed in many cancers. Specifically, Trastuzumab, which is a monoclonal antibody, is used against ErbB2, but its action mechanism is still unknown. ErbB2 can exist as both monomers and Homodimers, suggesting that Trastuzumab mechanims may be subtle. On the other hand, the membrane plays a role in the action mechanism of Trastuzumab but generates difficulties for structural studies. Coarse-Grained Molecular Dynamics has been used to study the influence of the Trastuzumab on the protein-protein and protein-membrane interactions of the full ErbB2 receptor. Our simulations start from conformations which both extracelullar and intracelullar domains are extended. The results show in both monomers and homodimers systems a folded conformation on the membrane: several experimental results, mainly obtained on ErbB1 support them. The protein-protein interaction on transmembrane and juxtamembrane domains are disrupted on the dimer and disordered on the monomer by the Trastuzumab effect, therefore, the dimerization-driven activation are unfavourable. We present a detailed description of the type of interactions governing the homodimerization and antobody complexation phenomena and the role that the membrane plays on that.

  • 13.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Widengren, Jerker
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Measuring hearing organ vibration patterns with confocal microscopy and optical flow2004In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 86, no 1 Pt 1, p. 535-543Article in journal (Refereed)
    Abstract [en]

    A new method for visualizing vibrating structures is described. The system provides a means to capture very fast repeating events by relatively minor modifications to a standard confocal microscope. An acousto-optic modulator was inserted in the beam path, generating brief pulses of laser light. Images were formed by summing consecutive frames until every pixel of the resulting image had been exposed to a laser pulse. Images were analyzed using a new method for optical flow computation; it was validated through introducing artificial displacements in confocal images. Displacements in the range of 0.8 to 4 pixels were measured with 5% error or better. The lower limit for reliable motion detection was 20% of the pixel size. These methods were used for investigating the motion pattern of the vibrating hearing organ. In contrast to standard theory, we show that the organ of Corti possesses several degrees of freedom during sound-evoked vibration. Outer hair cells showed motion indicative of deformation. After acoustic overstimulation, supporting cells contracted. This slowly developing structural change was visualized during simultaneous intense sound stimulation and its speed measured with the optical flow technique.

  • 14.
    Hammarström, Per
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Owenius, Rikard
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Mårtensson, Lars-Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Lindgren, M
    High-resolution probing of local conformational changes in proteins by the use of multiple labeling: Unfolding and self-assembly of human carbonic anhydrase II monitored by spin, fluorescent, and chemical reactivity probes2001In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 80, no 6, p. 2867-2885Article in journal (Refereed)
    Abstract [en]

    Two different spin labels, N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide (IPSL) and (1-oxyl-2.2,5,5-tetramethylpyrroline-3-methyl) methanethiosulfonate (MTSSL), and two different fluorescent labels 5-((((2-iodoacetyl)amino)ethyl)amino)naphtalene-1 -sulfonic acid (IAEDANS) and 6-bromoacetyl-2-dimetylaminonaphtalene (BADAN), were attached to the introduced C79 in human carbonic anhydrase (HCA II) to probe local structural changes upon unfolding and aggregation, HCA II unfolds in a multi-step manner with an intermediate state populated between the native and unfolded states. The spin label IPSL and the fluorescent label IAEDANS reported on a substantial change in mobility and polarity at both unfolding transitions at a distance of 7.4-11.2 Angstrom from the backbone of position 79. The shorter and less flexible labels BADAN and MTSSL revealed less pronounced spectroscopic changes in the native-to-intermediate transition, 6.6-9.0 Angstrom from the backbone. At intermediate guanidine (Gu)-HCl concentrations the occurrence of soluble but irreversibly aggregated oligomeric protein was identified from refolding experiments. At similar to1 M Gu-HCl the aggregation was found to be essentially complete. The size and structure of the aggregates could be varied by changing the protein concentration. EPR measurements and line-shape simulations together with fluorescence lifetime and anisotropy measurements provided a picture of the self-assembled protein as a disordered protein structure with a representation of both compact as well as dynamic and polar environments at the site of the molecular labels. This suggests that a partially folded intermediate of HCA II self-assembles by both local unfolding and intermolecular docking of the intermediates vicinal to position 79. The aggregates were determined to be 40-90 Angstrom in diameter depending on the experimental conditions and spectroscopic technique used.

  • 15.
    Hammarström, Per
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Persson, M
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Compactness measurements at unfolding of carbonic anhydrase by Trp-AEDANS fluorescence energy transfer. Evidence for forced unfolding by GroEL.2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 203Pos-Conference paper (Other academic)
  • 16. He, Wenxuan
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Ren, Tianying
    Fast reverse propagation of sound in the living cochlea2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 11, p. 2497-2505Article in journal (Refereed)
    Abstract [en]

    The auditory sensory organ, the cochlea, not only detects but also generates sounds. Such sounds, otoacoustic emissions, are widely used for diagnosis of hearing disorders and to estimate cochlear nonlinearity. However, the fundamental question of how the otoacoustic emission exits the cochlea remains unanswered. In this study, emissions were provoked by two tones with a constant frequency ratio, and measured as vibrations at the basilar membrane and at the stapes, and as sound pressure in the ear canal. The propagation direction and delay of the emission were determined by measuring the phase difference between basilar membrane and stapes vibrations. These measurements show that cochlea-generated sound arrives at the stapes earlier than at the measured basilar membrane location. Data also show that basilar membrane vibration at the emission frequency is similar to that evoked by external tones. These results conflict with the backward-traveling-wave theory and suggest that at low and intermediate sound levels, the emission exits the cochlea predominantly through the cochlear fluids.

  • 17.
    Huber, M
    et al.
    Leiden Univ, Dept Mol Phys, NL-2300 RA Leiden, Netherlands Inst Phys & Measurement Technol, Linkoping, Sweden.
    Owenius, Rikard
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Mårtensson, Lars-Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    High-field (95 GHz) EPR on spin labels in human carbonic anhydrase II: Perspectives of pulsed and CW EPR2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 182Pos-Conference paper (Other academic)
  • 18. Jacob, Stefan
    et al.
    Pienkowski, Martin
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    The endocochlear potential alters cochlear micromechanics2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 11, p. 2586-2594Article in journal (Refereed)
    Abstract [en]

    Acoustic stimulation gates mechanically sensitive ion channels in cochlear sensory hair cells. Even in the absence of sound, a fraction of these channels remains open, forming a conductance between hair cells and the adjacent fluid space, scala media. Restoring the lost endogenous polarization of scala media in an in vitro preparation of the whole cochlea depolarizes the hair cell soma. Using both digital laser interferometry and time-resolved confocal imaging, we show that this causes a structural refinement within the organ of Corti that is dependent on the somatic electromotility of the outer hair cells (OHCs). Specifically, the inner part of the reticular lamina up to the second row of OHCs is pulled toward the basilar membrane, whereas the outer part (third row of OHCs and the Hensen's cells) unexpectedly moves in the opposite direction. A similar differentiated response pattern is observed for sound-evoked vibrations: restoration of the endogenous polarization decreases vibrations of the inner part of the reticular lamina and results in up to a 10-fold increase of vibrations of the outer part. We conclude that the endogenous polarization of scala media affects the function of the hearing organ by altering its geometry, mechanical and electrical properties.

  • 19.
    Jonsson, Bengt-Harald
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Liljas, Anders
    Lund Univ, Sweden.
    Comments to the Editor Due to the Response by the Supuran Group to Our Article2021In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 120, no 1, p. 182-183Article in journal (Other academic)
    Abstract [en]

    n/a

  • 20.
    Jonsson, Bengt-Harald
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Liljas, Anders
    Lund Univ, Sweden.
    Perspectives on the Classical Enzyme Carbonic Anhydrase and the Search for Inhibitors2020In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 119, no 7, p. 1275-1280Article, review/survey (Refereed)
    Abstract [en]

    Carbonic anhydrase (CA) is a thoroughly studied enzyme. Its primary role is the rapid interconversion of carbon dioxide and bicarbonate in the cells, where carbon dioxide is produced, and in the lungs, where it is released from the blood. At the same time, it regulates pH homeostasis. The inhibitory function of sulfonamides on CA was discovered some 80 years ago. There are numerous physiological-therapeutic conditions in which inhibitors of carbonic anhydrase have a positive effect, such as glaucoma, or act as diuretics. With the realization that several isoenzymes of carbonic anhydrase are associated with the development of several types of cancer, such as brain and breast cancer, the development of inhibitor drugs specific to those enzyme forms has exploded. We would like to highlight the breadth of research on the enzyme as well as draw the attention to some problems in recent published work on inhibitor discovery.

  • 21.
    Jonsson, Peter
    et al.
    Division of Solid State Physics, Lund University, SE-22100 Lund, Sweden.
    Jonsson, Magnus P.
    Division of Solid State Physics, Lund University, SE-22100 Lund, Sweden.
    Tegenfeldt, Jonas O.
    Division of Solid State Physics, Lund University, SE-22100 Lund, Sweden.
    Hook, Fredrik
    Division of Solid State Physics, Lund University, SE-22100 Lund, Sweden.
    A Method Improving the Accuracy of Fluorescence Recovery after Photobleaching Analysis2008In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 11, p. 5334-5348Article in journal (Refereed)
    Abstract [en]

    Fluorescence recovery after photobleaching has been an established technique of quantifying the mobility of molecular species in cells and cell membranes for more than 30 years. However, under nonideal experimental conditions, the current methods of analysis still suffer from occasional problems; for example, when the signal/noise ratio is low, when there are temporal fluctuations in the illumination, or when there is bleaching during the recovery process. We here present a method of analysis that overcomes these problems, yielding accurate results even under nonideal experimental conditions. The method is based on circular averaging of each image, followed by spatial frequency analysis of the averaged radial data, and requires no prior knowledge of the shape of the bleached area. The method was validated using both simulated and experimental fluorescence recovery after photobleaching data, illustrating that the diffusion coefficient of a single diffusing component can be determined to within similar to 1%, even for small signal levels (100 photon counts), and that at typical signal levels (5000 photon counts) a system with two diffusion coefficients can be analyzed with less than 10% error.

  • 22.
    Karlsson, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Carlsson, Uno
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Protein adsorption orientation in the light of fluorescent probes: mapping of the interaction between site-directly labeled human carbonic anhydrase II and silica nanoparticles2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 5, p. 3536-3544Article in journal (Refereed)
    Abstract [en]

    Little is known about the direction and specificity of protein adsorption to solid surfaces, a knowledge that is of great importance in many biotechnological applications. To resolve the direction in which a protein with known structure and surface potentials binds to negatively charged silica nanoparticles, fluorescent probes were attached to different areas on the surface of the protein human carbonic anhydrase II. By this approach it was clearly demonstrated that the adsorption of the native protein is specific to limited regions at the surface of the N-terminal domain of the protein. Furthermore, the adsorption direction is strongly pH-dependent. At pH 6.3, a histidine-rich area around position 10 is the dominating adsorption region. At higher pH values, when the histidines in this area are deprotonated, the protein is also adsorbed by a region close to position 37, which contains several lysines and arginines. Clearly the adsorption is directed by positively charged areas on the protein surface toward the negatively charged silica surface at conditions when specific binding occurs.

  • 23.
    Klement, G.
    et al.
    Nobel Institute for Neurophysiology, Dept. of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nilsson, J.
    Nobel Institute for Neurophysiology, Dept. of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Arhem, P.
    Århem, P., Nobel Institute for Neurophysiology, Dept. of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A tyrosine substitution in the cavity wall of a K channel induces an inverted inactivation2008In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 94, no 8, p. 3014-3022Article in journal (Refereed)
    Abstract [en]

    Ion permeation and gating kinetics of voltage-gated K channels critically depend on the amino-acid composition of the cavity wall. Residue 470 in the Shaker K channel is an isoleucine, making the cavity volume in a closed channel insufficiently large for a hydrated K+ ion. In the cardiac human ether-a-go-go-related gene channel, which exhibits slow activation and fast inactivation, the corresponding residue is tyrosine. To explore the role of a tyrosine at this position in the Shaker channel, we studied I470Y. The activation became slower, and the inactivation faster and more complex. At +60 mV the channel inactivated with two distinct rates (t1 = 20 ms, t2 = 400 ms). Experiments with tetraethylammonium and high K + concentrations suggest that the slower component was of the P/C-type. In addition, an inactivation component with inverted voltage dependence was introduced. A step to -40 mV inactivates the channel with a time constant of 500 ms. Negative voltage steps do not cause the channel to recover from this inactivated state (t » 10 min), whereas positive voltage steps quickly do (t = 2 ms at +60 mV). The experimental findings can be explained by a simple branched kinetic model with two inactivation pathways from the open state. © 2008 by the Biophysical Society.

  • 24.
    Lee, Eric H
    et al.
    Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois; Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois.
    Hsin, Jen
    Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois.
    von Castelmur, Eleonore
    School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.
    Mayans, Olga
    School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.
    Schulten, Klaus
    Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois; Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IllinoisN.
    Tertiary and Secondary Structure Elasticity of a Six-Ig Titin Chain2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 6, p. 1085-1095Article in journal (Refereed)
    Abstract [en]

    The protein titin functions as a mechanical spring conferring passive elasticity to muscle. Force spectroscopy studies have shown that titin exhibits several regimes of elasticity. Disordered segments bring about a soft, entropic spring-type elasticity; secondary structures of titin's immunoglobulin-like (Ig-) and fibronectin type III-like (FN-III) domains provide a stiff elasticity. In this study, we demonstrate a third type of elasticity due to tertiary structure and involving domain-domain interaction and reorganization along the titin chain. Through 870 ns of molecular dynamics simulations involving 29,000-635,000 atom systems, the mechanical properties of a six-Ig domain segment of titin (I65-I70), for which a crystallographic structure is available, are probed. The results reveal a soft tertiary structure elasticity. A remarkably accurate statistical mechanical description for this elasticity is derived and applied. Simulations also studied the stiff, secondary structure elasticity of the I65-I70 chain due to the unraveling of its domains and revealed how force propagates along the chain during the secondary structure elasticity response.

  • 25.
    Lindgren, Mikael
    et al.
    Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
    Sörgjerd, Karin
    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.
    Detection and characterization of aggregates, prefibrillar amyloidogenic oligomers, and protofibrils using fluorescence spectroscopy2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 6, p. 4200-4212Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a protein linked to a number of different amyloid diseases including senile systemic amyloidosis and familial amyloidotic polyneuropathy. The transient nature of oligomeric intermediates of misfolded TTR that later mature into fibrillar aggregates makes them hard to study, and methods to study these species are sparse. In this work we explore a novel pathway for generation of prefibrillar aggregates of TTR, which provides important insight into TTR misfolding. Prefibrillar amyloidogenic oligomers and protofibrils of misfolded TTR were generated in vitro through induction of the molten globule type A-state from acid unfolded TTR through the addition of NaCl. The aggregation process produced fairly monodisperse oligomers (300–500 kD) within 2 h that matured after 20 h into larger spherical clusters (30–50 nm in diameter) and protofibrils as shown by transmission electron microscopy. Further maturation of the aggregates showed shrinkage of the spheres as the fibrils grew in length, suggesting a conformational change of the spheres into more rigid structures. The structural and physicochemical characteristics of the aggregates were investigated using fluorescence, circular dichroism, chemical cross-linking, and transmission electron microscopy. The fluorescent dyes 1-anilinonaphthalene-8-sulfonate (ANS), 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS), 4-(dicyanovinyl)-julolidine (DCVJ), and thioflavin T (ThT) were employed in both static and kinetic assays to characterize these oligomeric and protofibrillar states using both steady-state and time-resolved fluorescence techniques. DCVJ, a molecular rotor, was employed for the first time for studies of an amyloidogenic process and is shown useful for detection of the early steps of the oligomerization process. DCVJ bound to the early prefibrillar oligomers (300–500 kD) with an apparent dissociation constant of 1.6 mM, which was slightly better than for ThT (6.8 mM). Time-resolved fluorescence anisotropy decay of ANS was shown to be a useful tool for giving further structural and kinetic information of the oligomeric aggregates. ThT dramatically increases its fluorescence quantum yield when bound to amyloid fibrils; however, the mechanism behind this property is unknown. Data from this work suggest that unbound ThT is also intrinsically quenched and functions similarly to a molecular rotor, which in combination with its environmental dependence provides a blue shift to the characteristic 482nm wavelength when bound to amyloid fibrils.

  • 26.
    Loitto, Vesa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Dysregulation of aquaporins impairs neutrophil leukocyte motility2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 2, p. 519A-519AConference paper (Other academic)
  • 27.
    Neudecker, Philipp
    et al.
    University of Toronto, Ontario, Canada.
    Lundström, Patrik
    University of Toronto, Ontario, Canada.
    Kay, Lewis E.
    University of Toronto, Ontario, Canada.
    Relaxation Dispersion NMR Spectroscopy as a Tool for Detailed Studies of Protein Folding2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 6, p. 2045-2054Article in journal (Refereed)
    Abstract [en]

    Characterization of the mechanisms by which proteins fold into their native conformations is important not only for protein structure prediction and design but also because protein misfolding intermediates may play critical roles in fibril formation that are commonplace in neurodegenerative disorders. In practice, the study of folding pathways is complicated by the fact that for the most part intermediates are low-populated and short-lived so that biophysical studies are difficult. Due to recent methodological advances, relaxation dispersion NMR spectroscopy has emerged as a particularly powerful tool to obtain high-resolution structural information about protein folding events on the millisecond timescale. Applications of the methodology to study the folding of SH3 domains have shown that folding proceeds via previously undetected on-pathway intermediates, sometimes stabilized by nonnative long-range interactions. The relaxation dispersion approach provides a detailed kinetic and thermodynamic description of the folding process as well as the promise of obtaining an atomic level structural description of intermediate states. We review the concerted application of a variety of recently developed NMR relaxation dispersion experiments to obtain a "high-resolution" picture of the folding pathway of the A39V/N53P/V55L Fyn SH3 domain.

  • 28.
    Nilsson, Johanna
    et al.
    Karolinska Institute.
    Madeja, Michael
    University of Munster, Germany.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arhem, Peter
    Karolinska Institute.
    Bupivacaine Blocks N-Type Inactivating K-v Channels in the Open State: No Allosteric Effect on Inactivation Kinetics2008In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 11, p. 5138-5152Article in journal (Refereed)
    Abstract [en]

    Local anesthetics bind to ion channels in a state-dependent manner. For noninactivating voltage-gated K channels the binding mainly occurs in the open state, while for voltage-gated inactivating Na channels it is assumed to occur mainly in inactivated states, leading to an allosterically caused increase in the inactivation probability, reflected in a negative shift of the steady-state inactivation curve, prolonged recovery from inactivation, and a frequency-dependent block. How local anesthetics bind to N-type inactivating K channels is less explored. In this study, we have compared bupivacaine effects on inactivating (Shaker and K(v)3.4) and noninactivating (Shaker-IR and K(v)3.2) channels, expressed in Xenopus oocytes. Bupivacaine was found to block these channels time-dependently without shifting the steady-state inactivation curve markedly, without a prolonged recovery from inactivation, and without a frequency-dependent block. An analysis, including computational testing of kinetic models, suggests binding to the channel mainly in the open state, with affinities close to those estimated for corresponding noninactivating channels (300 and 280 mu M for Shaker and Shaker-IR, and 60 and 90 mu M for K(v)3.4 and K(v)3.2). The similar magnitudes of K-d, as well as of blocking and unblocking rate constants for inactivating and noninactivating Shaker channels, most likely exclude allosteric interactions between the inactivation mechanism and the binding site. The relevance of these results for understanding the action of local anesthetics on Na channels is discussed.

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  • 29.
    Owenius, Rikard
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Osterlund, Marie
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Svensson, Magdalena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Lindgren, M
    Persson, E
    Freskgård, Per-Ola
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Spin and fluorescent probing of the binding interface between tissue factor and factor VIIa at multiple sites2001In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 81, no 4, p. 2357-2369Article in journal (Refereed)
    Abstract [en]

    The specific complex between the extracellular part of tissue factor (sTF) and factor Vlla (FVlla) was chosen as a model for studies of the binding interface between two interacting proteins. Six surface-exposed positions in sTF, residues known to contribute to the sTF-FVlla interaction, were selected for cysteine mutation and site-directed labeling with spin and fluorescent probes. The binding interface was characterized by spectral data from electron paramagnetic resonance (EPR) and steady-state and time-domain fluorescence spectroscopy. The labels reported on compact local environments at positions 158 and 207 in the interface region between sTF and the gamma -carboxyglutamic acid (Gla) domain of FVlla, and at positions 22 and 140 in the interface region between sTF and the first epidermal growth factor-like (EGF1) domain of FVlla. The tightness of the local interactions in these parts of the interface is similar to that seen in the interior of globular proteins. This was further emphasized by the reduced local polarity detected by the fluorescent label upon FVlla binding, especially in the sTF-Gla region. There were indications of structural rigidity also at positions 45 and 94 in the interface region between sTF and the protease domain (PD) of FVlla, despite the perturbed cofactor function of these sTF variants. The results of the present study indicate that the multi-probing approach enables comparison of the tightness and characteristics of interaction along the binding interface of a protein complex. This approach also increases the probability of acquiring reliable structural data that are descriptive of the wild-type proteins.

  • 30. Persson, M
    et al.
    Zhou, A
    Mitri, R
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Eaton, GR
    Eaton, SS
    Distance determination between deeply buried position in human carbon anhydrase II2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 2255Pos-Conference paper (Other academic)
  • 31.
    Persson, Malin
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Harbridge, JR
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Mitri, R
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Mårtensson, Lars-Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Carlsson, Uno
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Eaton, GR
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Eaton, SS
    Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA Linkoping Univ, Dept Chem, IFM, SE-58183 Linkoping, Sweden.
    Comparison of electron paramagnetic resonance methods to determine distances between spin labels on human carbonic anhydrase II2001In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 80, no 6, p. 2886-2897Article in journal (Refereed)
    Abstract [en]

    Four doubly spin-labeled variants of human carbonic anhydrase II and corresponding singly labeled variants were prepared by site-directed spin labeling. The distances between the spin labels were obtained from continuous-wave electron paramagnetic resonance spectra by analysis of the relative intensity of the half-field transition, Fourier deconvolution of line-shape broadening, and computer simulation of line-shape changes. Distances also were determined by four-pulse double electron-electron resonance. For each variant, at least two methods were applicable and reasonable agreement between methods was obtained. Distances ranged from 7 to 24 W. The doubly spin-labeled samples contained some singly labeled protein due to incomplete labeling. The sensitivity of each of the distance determination methods to the noninteracting component was compared.

  • 32.
    Schwaiger, Christine S.
    et al.
    Royal Institute of Technology, KTH, Sweden .
    Liin, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindahl, Erik
    Royal Institute of Technology, KTH, Sweden .
    The Conserved Phenylalanine in the K+ Channel Voltage-Sensor Domain Creates a Barrier with Unidirectional Effects2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 1, p. 75-84Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels are crucial for regulation of electric activity of excitable tissues such as nerve cells, and play important roles in many diseases. During activation, the charged S4 segment in the voltage sensor domain translates across a hydrophobic core forming a barrier for the gating charges. This barrier is critical for channel function, and a conserved phenylalanine in segment S2 has previously been identified to be highly sensitive to substitutions. Here, we have studied the kinetics of K(v)1-type potassium channels (Shaker and K(v)1.2/2.1 chimera) through site-directed mutagenesis, electrophysiology, and molecular simulations. The F290L mutation in Shaker (F233L in K(v)1.2/2.1) accelerates channel closure by at least a factor 50, although opening is unaffected. Free energy profiles with the hydrophobic neighbors of F233 mutated to alanine indicate that the open state with the fourth arginine in S4 above the hydrophobic core is destabilized by similar to 17 kJ/mol compared to the first closed intermediate. This significantly lowers the barrier of the first deactivation step, although the last step of activation,is unaffected. Simulations of wild-type F233 show that the phenyl ring always rotates toward the extracellular side both for activation and deactivation, which appears to help stabilize a well-defined open state.

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  • 33. Taniguchi, K
    et al.
    Kaya, S
    Yokoyama, T
    Abe, K
    Katoh, T
    Yazawa, M
    Hayashi, Y
    Mårdh, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    New aspects of Na/K-ATPase, Acid labile ATP and/or ADP/Pi binding to the tetraprotomer2000In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 78, no 1, p. 447Pos-Conference paper (Other academic)
  • 34.
    Tomo, Igor
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-evoked radial strain in the hearing organ2007In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 93, no 9, p. 3279-3284Article in journal (Refereed)
    Abstract [en]

    The hearing organ contains sensory hair cells, which convert sound-evoked vibration into action potentials in the auditory nerve. This process is greatly enhanced by molecular motors that reside within the outer hair cells, but the performance also depends on passive mechanical properties, such as the stiffness, mass, and friction of the structures within the organ of Corti. We used resampled confocal imaging to study the mechanical properties of the low-frequency regions of the cochlea. The data allowed us to estimate an important mechanical parameter, the radial strain, which was found to be 0.1% near the inner hair cells and 0.3% near the third row of outer hair cells during moderate-level sound stimulation. The strain was caused by differences in the motion trajectories of inner and outer hair cells. Motion perpendicular to the reticular lamina was greater at the outer hair cells, but inner hair cells showed greater radial vibration. These differences led to deformation of the reticular lamina, which connects the apex of the outer and inner hair cells. These results are important for understanding how the molecular motors of the outer hair cells can so profoundly affect auditory sensitivity.

  • 35. Zheng, Jiefu
    et al.
    Ramamoorthy, Sripriya
    Ren, Tianying
    He, Wenxuan
    Zha, Dingjun
    Chen, Fangyi
    Magnusson, Anna
    Nuttall, Alfred L
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Persistence of past stimulations: storing sounds within the inner ear2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 7, p. 1627-1634Article in journal (Refereed)
    Abstract [en]

    Tones cause vibrations within the hearing organ. Conventionally, these vibrations are thought to reflect the input and therefore end with the stimulus. However, previous recordings of otoacoustic emissions and cochlear microphonic potentials suggest that the organ of Corti does continue to move after the end of a tone. These after-vibrations are characterized here through recordings of basilar membrane motion and hair cell extracellular receptor potentials in living anesthetized guinea pigs. We show that after-vibrations depend on the level and frequency of the stimulus, as well as on the sensitivity of the ear. Even a minor loss of hearing sensitivity caused a sharp reduction in after-vibration amplitude and duration. Mathematical models suggest that after-vibrations are driven by energy added into organ of Corti motion after the end of an acoustic stimulus. The possible importance of after-vibrations for psychophysical phenomena such as forward masking and gap detection are discussed.

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