Enhancement of Chaperone Function of α-Crystallin by Methylglyoxal Modification

Citations Over TimeTop 11% of 2003 papers

Abstract

The molecular chaperone function of α-crystallin in the lens prevents the aggregation and insolubilization of lens proteins that occur during the process of aging. We found that chemical modification of α-crystallin by a physiological α-dicarbonyl compound, methylglyoxal (MG), enhances its chaperone function. Protein-modifying sugars and ascorbate have no such effect and actually reduce chaperone function. Chaperone assay after immunoprecipitation or with immunoaffinity-purified argpyrimidine-α-crystallin indicates that 50−60% of the increased chaperone function is due to argpyrimidine-modified protein. Incubation of α-crystallin with dl-glyceraldehyde and arginine-modifying agents also enhances chaperone function, and we believe that the increased chaperone activity depends on the extent of arginine modification. Far- and near-UV circular dichroism spectra indicate modest changes in secondary and tertiary structure of MG-modified α-crystallin. LC MS/MS analysis of MG-modified α-crystallin following chymotryptic digestion revealed that R21, R49, and R103 in αA-crystallin were converted to argpyrimidine. 1,1‘-Bis(4-anilino)naphthalene-5,5‘-disulfonic acid binding, an indicator of hydrophobicity of proteins, increased in α-crystallin modified by low concentrations of MG (2−100 μM). MG similarly enhances chaperone function of another small heat shock protein, Hsp27. Our results show that posttranslational modification by a metabolic product can enhance the chaperone function of α-crystallin and Hsp27 and suggest that such modification may be a protective mechanism against environmental and metabolic stresses. Augmentation of the chaperone function of α-crystallin might have evolved to protect the lens from deleterious protein modifications associated with aging.

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