| First Author | Brennan LA | Year | 2009 |
| Journal | Biochim Biophys Acta | Volume | 1790 |
| Issue | 12 | Pages | 1665-72 |
| PubMed ID | 19733220 | Mgi Jnum | J:164844 |
| Mgi Id | MGI:4835387 | Doi | 10.1016/j.bbagen.2009.08.011 |
| Citation | Brennan LA, et al. (2009) Methionine sulfoxide reductase A (MsrA) restores alpha-crystallin chaperone activity lost upon methionine oxidation. Biochim Biophys Acta 1790(12):1665-72 |
| abstractText | 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 alpha-crystallin which is a two-subunit (alphaA and alphaB) chaperone. Here, we tested whether PMSO formation damages alpha-crystallin chaperone function and whether MsrA could repair PMSO-alpha-crystallin. METHODS: Total alpha-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-alpha-crystallin was treated with MsrA, and repair was assessed by CNBr cleavage, mass spectrometry and recovery of chaperone function. The levels of alpha-crystallin-PMSO in the lenses of MsrA-knockout relative to wild-type mice were determined. RESULTS: PMSO oxidation of total alpha-crystallin (met 138 of alphaA and met 68 of alphaB) resulted in loss of alpha-crystallin chaperone activity. MsrA treatment of PMSO-alpha-crystallin repaired its chaperone activity through reduction of PMSO. Deletion of MsrA in mice resulted in increased levels of PMSO-alpha-crystallin. CONCLUSIONS: Methionine oxidation damages alpha-crystallin chaperone function and MsrA can repair PMSO-alpha-crystallin restoring its chaperone function. MsrA is required for maintaining the reduced state of alpha-crystallin methionines in the lens. SIGNIFICANCE: Methionine oxidation of alpha-crystallin in combination with loss of MsrA repair causes loss of alpha-crystallin chaperone function. Since increased PMSO levels and loss of alpha-crystallin function are hallmarks of cataract, these results provide insight into the mechanisms of cataract development and likely those of other age-related diseases. |
