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  • 1.
    Hennig, Janosch
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology. Helmholtz Zentrum Munchen GmbH, Germany; Technical University of Munich, Germany.
    Andrésen, Cecilia
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Museth, Anna Katrine
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology. CALTECH, CA 91125 USA.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Tibell, Lena
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Local Destabilization of the Metal-Binding Region in Human Copper-Zinc Superoxide Dismutase by Remote Mutations Is a Possible Determinant for Progression of ALS2015In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 54, no 2, p. 323-333Article in journal (Refereed)
    Abstract [en]

    More than 100 distinct mutations in the gene CuZnSOD encoding human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS), a fatal neuronal disease. Many studies of different mutant proteins have found effects on protein stability, catalytic activity, and metal binding, but without a common pattern. Notably, these studies were often performed under conditions far from physiological. Here, we have used experimental conditions of pH 7 and 37 degrees C and at an ionic strength of 0.2 M to mimic physiological conditions as close as possible in a sample of pure protein. Thus, by using NMR spectroscopy, we have analyzed amide hydrogen exchange of the fALS-associated I113T CuZnSOD variant in its fully metalated state, both at 25 and 37 degrees C, where (15)N relaxation data, as expected, reveals that CuZnSOD I113T exists as a dimer under these conditions. The local dynamics at 82% of all residues have been analyzed in detail. When compared to the wild-type protein, it was found that I113T CuZnSOD is particularly destabilized locally at the ion binding sites of loop 4, the zinc binding loop, which results in frequent exposure of the aggregation prone outer beta-strands I and VI of the beta-barrel, possibly enabling fibril or aggregate formation. A similar study (Museth, A. K., et al. (2009) Biochemistry, 48, 8817-8829) of amide hydrogen exchange at pH 7 and 25 degrees C on the G93A variant also revealed a selective destabilization of the zinc binding loop. Thus, a possible scenario in ALS is that elevated local dynamics at the metal binding region can result in toxic species from formation of new interactions at local beta-strands.

  • 2.
    Miller, Jeremiah E.
    et al.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Di Bilio, Angel J.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Wehbi, William A.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Green, Michael T.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Museth, Anna Katrine
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Richards, John R.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Winkler, Jay R.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Gray, Harry B.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Electron tunneling in rhenium-modified Pseudomonas aeruginosa azurins2004In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1655, no 1-3, p. 59-63Article in journal (Refereed)
    Abstract [en]

    Laser flash-quench methods have been used to generate tyrosine and tryptophan radicals in structurally characterized rhenium-modified Pseudomonas aeruginosa azurins. Cu(I) to “Re(II)” electron tunneling in Re(H107) azurin occurs in the microsecond range. This reaction is much faster than that studied previously for Cu(I) to Ru(III) tunneling in Ru(H107) azurin, suggesting that a multistep (“hopping”) mechanism might be involved. Although a Y108 radical can be generated by flash-quenching a Re(H107)M(II) (M=Cu, Zn) protein, the evidence suggests that it is not an active intermediate in the enhanced Cu(I) oxidation. Rather, the likely explanation is rapid conversion of Re(II)(H107) to deprotonated Re(I)(H107 radical), followed by electron tunneling from Cu(I) to the hole in the imidazole ligand.

  • 3.
    Museth, Anna Katrine
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Characterization of folding dynamics and accelerated electron transfer in proteins2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The research presented in this thesis is divided in two: The first part is a study of the intracellular protein human copper zinc superoxide dismutase which has been associated with the fatale disease Amyotrophic lateral Selerosis (ALS). ALS is a progressive neurodegenerative disease of motor neurons, and in the cases where the disease is inheriled (fALS), roughly 15% is caused by mutations in human copper·zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 causes ALS is still unknown, but it is believed that mutant CuZnSOD proteins misfold followed by aggregation into high molecular species that ultimately lead to the death of motor neurons. In our study we have investigated the dynamical and structural differences between the wt of CuZnSOD and the ALS-associated variant G93A. 1H-15N·HSQC NMR spectroscopy was used to analyze hydrogen deuterium exchange at the backbone amide groups. The study showed that the mutation selectively destabilizes the remote metal binding region. This suggests that the metal binding region might be involved in intermolecular protein-protein interactions which may constitule the eariy stages in formation of aggregates. In another of our studies the monomer to dimer equilibrium as weil as the catalytic activity is investigated upon protein denaturation using CdmCI. The study showed persistent dimer interactions and high catalytic activity at GdmCllevels where the holo-protein according to CD measurements is fully unfolded.

    The second part of this thesis focuses on electron transfer (ET) in proteins. ET processes are fundamental in many biological processes such as respiration and photosynthesis. Biological ET reactions occur rapidly over large molecular distances (>20Å) and only minor structural changes around the active site arises during the ET event. Previous work on Rumodified P. aeruginosa azurin have demonstrated that optimized electron coupling through a θ-strand yield a distance decay constant of 1.1 Å-1. ET in biological systems often requires sub-millisecond charge transport over long molecular distances (>20A). This is not possible via direct tunneling through a θ-strand. It is believed that ET rates can be greatly enhanced by multistep tunneling ("hopping") in which redox-active amino acid side-chains act as intermediate donors or acceptors. In our work, rapid spectroscopic methods are used to investigate hopping through an intermediate tryptophan or tyrosine radical. Cu(l) to Re(II) electron tunneling in Re(H107) azurin occurs in the microsecond range, which is much faster than for previously studied Cu(l) to Ru(III) tunneling in Ru(H107). At first it was believed to be multistep tunneling, but further investigation disproved this. A more likely explanalion is rapid conversion of Re(II)(H107) to deprotonated Re(I)(H107 radieal), followed by electron tunneling from Cu(l) to the hole in the imidazole Iigand. In the other investigated system Cu(l) oxidation by a photoexcited Re(l) diimine at position 124 on a ß-strand (His124-Gly123-Trp122-Met121) takes place in nanoseconds, which is remarkable and more than two orders of magnitude faster than for single-step ET at a 19 Adonoracceptor distance. This system is the first model system to show that an intervening tryptophan residue between donor and acceptor can accelerate the ET rate. Therefore this work was published in Science.

    List of papers
    1. Selective destabilization of the metal binding region caused by the FALS associated mutation G93A in CuZnSOD
    Open this publication in new window or tab >>Selective destabilization of the metal binding region caused by the FALS associated mutation G93A in CuZnSOD
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We have, by use of 1H-15N-HSQC NMR spectroscopy, analyzed hydrogen exchange at the amide groups of wtCuZnSOD and the FALS-associated G93A SOD-variant in their fully metallated states. From measurements at near physiological conditions we could analyze the exchange at 64% of all backbone amide groups, which have allowed a detailed characterization of the local dynamics at these positions in both the wt and G93A proteins. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However the mutation results in local destabilization at the site of mutation and to stabilization at positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may be involved in intermolecular protein-protein interactions, which may constitute the early stages in formation of aggregates.

    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-85309 (URN)
    Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2016-05-04
    2. The equilibrium between the monomer and dimer form of ALS-related SOD1 mutants
    Open this publication in new window or tab >>The equilibrium between the monomer and dimer form of ALS-related SOD1 mutants
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    No abstract available.

    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-85310 (URN)
    Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2016-05-04
    3. Electron tunneling in rhenium-modified Pseudomonas aeruginosa azurins
    Open this publication in new window or tab >>Electron tunneling in rhenium-modified Pseudomonas aeruginosa azurins
    Show others...
    2004 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1655, no 1-3, p. 59-63Article in journal (Refereed) Published
    Abstract [en]

    Laser flash-quench methods have been used to generate tyrosine and tryptophan radicals in structurally characterized rhenium-modified Pseudomonas aeruginosa azurins. Cu(I) to “Re(II)” electron tunneling in Re(H107) azurin occurs in the microsecond range. This reaction is much faster than that studied previously for Cu(I) to Ru(III) tunneling in Ru(H107) azurin, suggesting that a multistep (“hopping”) mechanism might be involved. Although a Y108 radical can be generated by flash-quenching a Re(H107)M(II) (M=Cu, Zn) protein, the evidence suggests that it is not an active intermediate in the enhanced Cu(I) oxidation. Rather, the likely explanation is rapid conversion of Re(II)(H107) to deprotonated Re(I)(H107 radical), followed by electron tunneling from Cu(I) to the hole in the imidazole ligand.

    Keywords
    Electron tunneling, Rhenium complex, Amino acid radical, Blue copper, Azurin
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-85311 (URN)10.1016/j.bbabio.2003.06.010 (DOI)
    Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2017-12-07
    4. Tryptophan-accelerated electron flow through proteins
    Open this publication in new window or tab >>Tryptophan-accelerated electron flow through proteins
    Show others...
    2008 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 320, no 5884, p. 1760-1762Article in journal (Refereed) Published
    Abstract [en]

    Energy flow in biological structures often requires submillisecond charge transport over long molecular distances. Kinetics modeling suggests that charge-transfer rates can be greatly enhanced by multistep electron tunneling in which redox-active amino acid side chains act as intermediate donors or acceptors. We report transient optical and infrared spectroscopic experiments that quantify the extent to which an intervening tryptophan residue can facilitate electron transfer between distant metal redox centers in a mutant Pseudomonas aeruginosa azurin. CuI oxidation by a photoexcited ReI-diimine at position 124 on a histidine(124)-glycine(123)-tryptophan(122)-methionine(121) β strand occurs in a few nanoseconds, fully two orders of magnitude faster than documented for single-step electron tunneling at a 19 angstrom donor-acceptor distance.

    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-85312 (URN)10.1126/science.1158241 (DOI)
    Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2017-12-07
  • 4.
    Museth, Anna Katrine
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Brorsson, Anna-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Tibell, Lena A. E.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Selective destabilization of the metal binding region caused by the FALS associated mutation G93A in CuZnSODManuscript (preprint) (Other academic)
    Abstract [en]

    We have, by use of 1H-15N-HSQC NMR spectroscopy, analyzed hydrogen exchange at the amide groups of wtCuZnSOD and the FALS-associated G93A SOD-variant in their fully metallated states. From measurements at near physiological conditions we could analyze the exchange at 64% of all backbone amide groups, which have allowed a detailed characterization of the local dynamics at these positions in both the wt and G93A proteins. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However the mutation results in local destabilization at the site of mutation and to stabilization at positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may be involved in intermolecular protein-protein interactions, which may constitute the early stages in formation of aggregates.

  • 5.
    Museth, Anna Katrine
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Tibell, Lena
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    The ALS-Associated Mutation G93A in Human Copper-Zinc Superoxide Dismutase Selectively Destabilizes the Remote Metal Binding Region2009In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 48, no 37, p. 8817-8829Article in journal (Refereed)
    Abstract [en]

    More than 100 distinct mutations in the gene (SOD 1) for human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS). Studies of these mutant proteins, which often have been performed under far from physiological conditions, have indicated effects oil protein stabilities, catalytic activity, kind metal binding affinities but with no common pattern. Also, with the knowledge that ALS is a late onset disease it is apparent that protein interactions which contribute to the disorder might, in the natural cellular milieu, depend on a delicate balance between intrinsic protein properties. In this study, we have used experimental conditions as near as possible to the in vivo conditions to reduce artifacts emanating from the experimental setup. Using H-1-N-15 HSQC NMR spectroscopy, we have analyzed hydrogen exchange at the amide groups of wild-type (wt) CuZnSOD and the fALS-associated G93A SOD variant in their fully metalated states. From analyses of the exchange pattern, we have characterized the local dynamics at 64% of all positions in detail in both the wt and G93A protein. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However, the mutation results in local destabilization at the site of the Mutation and also in stabilization at a few positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may affect the intermolecular protein-protein interactions which cause formation of protein aggregates.

  • 6.
    Museth, Anna Katrine
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Tibell, Lena A. E.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    The equilibrium between the monomer and dimer form of ALS-related SOD1 mutantsManuscript (preprint) (Other academic)
    Abstract [en]

    No abstract available.

  • 7.
    Shih, Crystal
    et al.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Museth, Anna Katrine
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Abrahamsson, Malin
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Blanco-Rodriguez, Ana Maria
    School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
    Di Bilio, Angel J.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Sudhamsu, Jawahar
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, USA.
    Crane, Brian R.
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, USA.
    Ronayne, Kate L.
    Central Laser Facility, STFC Rutherford Appleton Laboratory, Chilton, Didcot, Oxfordshire, UK.
    Towrie, Mike
    Central Laser Facility, STFC Rutherford Appleton Laboratory, Chilton, Didcot, Oxfordshire, UK.
    Vlček Jr., Antonin
    School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
    Richards, John H.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Winkler, Jay R.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Gray, Harry B.
    Beckman Institute, California Institute of Technology, Pasadena, USA.
    Tryptophan-accelerated electron flow through proteins2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 320, no 5884, p. 1760-1762Article in journal (Refereed)
    Abstract [en]

    Energy flow in biological structures often requires submillisecond charge transport over long molecular distances. Kinetics modeling suggests that charge-transfer rates can be greatly enhanced by multistep electron tunneling in which redox-active amino acid side chains act as intermediate donors or acceptors. We report transient optical and infrared spectroscopic experiments that quantify the extent to which an intervening tryptophan residue can facilitate electron transfer between distant metal redox centers in a mutant Pseudomonas aeruginosa azurin. CuI oxidation by a photoexcited ReI-diimine at position 124 on a histidine(124)-glycine(123)-tryptophan(122)-methionine(121) β strand occurs in a few nanoseconds, fully two orders of magnitude faster than documented for single-step electron tunneling at a 19 angstrom donor-acceptor distance.

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