Methionine sulfoxide reductase A (MsrA) restores α-crystallin chaperone activity lost upon methionine oxidation

Lisa A. Brennan, Wanda Lee, Frank J. Giblin, Larry L. David, Marc Kantorow

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background: Lens cataract is associated with protein oxidation and aggregation. Two proteins that cause cataract when deleted from the lens are methionine sulfoxide reductase A (MsrA) that repairs protein methionine sulfoxide (PMSO) oxidized proteins and α-crystallin which is a two-subunit (αA and αB) chaperone. Here, we tested whether PMSO formation damages α-crystallin chaperone function and whether MsrA could repair PMSO-α-crystallin. Methods: Total α-crystallin was oxidized to PMSO and evaluated by CNBr-cleavage and mass spectrometry. Chaperone activity was measured by light scattering using lysozyme as target. PMSO-α-crystallin was treated with MsrA, and repair was assessed by CNBr cleavage, mass spectrometry and recovery of chaperone function. The levels of α-crystallin-PMSO in the lenses of MsrA-knockout relative to wild-type mice were determined. Results: PMSO oxidation of total α-crystallin (met 138 of αA and met 68 of αB) resulted in loss of α-crystallin chaperone activity. MsrA treatment of PMSO-α-crystallin repaired its chaperone activity through reduction of PMSO. Deletion of MsrA in mice resulted in increased levels of PMSO-α-crystallin. Conclusions: Methionine oxidation damages α-crystallin chaperone function and MsrA can repair PMSO-α-crystallin restoring its chaperone function. MsrA is required for maintaining the reduced state of α-crystallin methionines in the lens. Significance: Methionine oxidation of α-crystallin in combination with loss of MsrA repair causes loss of α-crystallin chaperone function. Since increased PMSO levels and loss of α-crystallin function are hallmarks of cataract, these results provide insight into the mechanisms of cataract development and likely those of other age-related diseases.

Original languageEnglish (US)
Pages (from-to)1665-1672
Number of pages8
JournalBiochimica et Biophysica Acta - General Subjects
Volume1790
Issue number12
DOIs
StatePublished - Dec 2009

Keywords

  • Cataract
  • Chaperone activity
  • Methionine sulfoxide reductase
  • Oxidative stress
  • α-crystallin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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