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Research article

Hotspots of age-related protein degradation: the importance of neighboring residues for the formation of non-disulfide crosslinks derived from cysteine

Michael G. Friedrich, Zhen Wang, Aaron J. Oakley, Kevin L. Schey, Roger J.W. Truscott
Biochemical Journal Jul 11, 2017, 474 (14) 2475-2487; DOI: 10.1042/BCJ20170268
Michael G. Friedrich
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2500, Australia
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  • For correspondence: michaelf@uow.edu.au
Zhen Wang
Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, U.S.A.
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Aaron J. Oakley
School of Chemistry, University of Wollongong, Wollongong, NSW 2500, Australia
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Kevin L. Schey
Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, U.S.A.
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Roger J.W. Truscott
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2500, Australia
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Abstract

Over time, the long-lived proteins that are present throughout the human body deteriorate. Typically, they become racemized, truncated, and covalently cross-linked. One reaction responsible for age-related protein cross-linking in the lens was elucidated recently and shown to involve spontaneous formation of dehydroalanine (DHA) intermediates from phosphoserine. Cys residues are another potential source of DHA, and evidence for this was found in many lens crystallins. In the human lens, some sites were more prone to forming non-disulfide covalent cross-links than others. Foremost among them was Cys5 in βA4 crystallin. The reason for this enhanced reactivity was investigated using peptides. Oxidation of Cys to cystine was a prerequisite for DHA formation, and DHA production was accelerated markedly by the presence of a Lys, one residue separated from Cys5. Modeling and direct investigation of the N-terminal sequence of βA4 crystallin, as well as a variety of homologous peptides, showed that the epsilon amino group of Lys can promote DHA production by nucleophilic attack on the alpha proton of cystine. Once a DHA residue was generated, it could form intermolecular cross-links with Lys and Cys. In the lens, the most abundant cross-link involved Cys5 of βA4 crystallin attached via a thioether bond to glutathione. These findings illustrate the potential of Cys and disulfide bonds to act as precursors for irreversible covalent cross-links and the role of nearby amino acids in creating ‘hotpsots’ for the spontaneous processes responsible for protein degradation in aged tissues.

  • cross-linking
  • human aging
  • lens
  • protein modification
  • Abbreviations

    DHA,
    dehydroalanine;
    HAL,
    histidinoalanine;
    LAL,
    lysinoalanine;
    LAN,
    lanthionine;
    LLP,
    long-lived protein;
    MD,
    molecular dynamics;
    PTMs,
    posttranslational modifications;
    USF,
    urea soluble fraction;
    WSF,
    water soluble fraction
    • © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
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    July 2017

    Volume: 474 Issue: 14

    Biochemical Journal: 474 (14)
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    Hotspots of age-related protein degradation: the importance of neighboring residues for the formation of non-disulfide crosslinks derived from cysteine
    Michael G. Friedrich, Zhen Wang, Aaron J. Oakley, Kevin L. Schey, Roger J.W. Truscott
    Biochemical Journal Jul 2017, 474 (14) 2475-2487; DOI: 10.1042/BCJ20170268
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    Hotspots of age-related protein degradation: the importance of neighboring residues for the formation of non-disulfide crosslinks derived from cysteine
    Michael G. Friedrich, Zhen Wang, Aaron J. Oakley, Kevin L. Schey, Roger J.W. Truscott
    Biochemical Journal Jul 2017, 474 (14) 2475-2487; DOI: 10.1042/BCJ20170268

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    Keywords

    cross-linking
    human aging
    lens
    protein modification

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