Abstract
Methylglyoxal (MGO) is an α-dicarbonyl compound present ubiquitously in the human body. MGO reacts with arginine residues in proteins and forms adducts such as hydroimidazolone and argpyrimidine in vivo. Previously, we showed that MGO-mediated modification of αA-crystallin increased its chaperone function. We identified MGO-modified arginine residues in αA-crystallin and found that replacing such arginine residues with alanine residues mimicked the effects of MGO on the chaperone function. Arginine 12 (R12) is a conserved amino acid residue in Hsp27 as well as αA- and αB-crystallin. When treated with MGO at or near physiological concentrations (2–10 µM), R12 was modified to hydroimidazolone in all three small heat shock proteins. In this study, we determined the effect of arginine substitution with alanine at position 12 (R12A to mimic MGO modification) on the structure and chaperone function of these proteins. Among the three proteins, the R12A mutation improved the chaperone function of only αA-crystallin. This enhancement in the chaperone function was accompanied by subtle changes in the tertiary structure, which increased the thermodynamic stability of αA-crystallin. This mutation induced the exposure of additional client protein binding sites on αA-crystallin. Altogether, our data suggest that MGO-modification of the conserved R12 in αA-crystallin to hydroimidazolone may play an important role in reducing protein aggregation in the lens during aging and cataract formation.
Highlights
Small heat shock proteins are a family of stress proteins. aCrystallin and Hsp27 are the major small heat shock proteins in humans
We have shown that MGO modifications of small heat shock proteins, such as aA-crystallin and Hsp27, enhanced their chaperone function [30,37]
Our primary goal was to determine whether a similar increase in the chaperone function occurred with physiological levels of MGO and to determine whether a modification of the conserved R12 (Fig. 2A) to hydroimidazolone contributed to the increased chaperone function
Summary
Small heat shock proteins are a family of stress proteins. aCrystallin and Hsp are the major small heat shock proteins in humans. ACrystallin and Hsp are the major small heat shock proteins in humans. Several studies have shown that these post-translational modifications decrease the chaperone function of a-crystallin, which might be one reason for lens aging and age-related cataract formation [13,14,15,16,17]. We replaced discrete MGO-modifiable arginine residues with a neutral amino acid, alanine, and showed an improvement in the chaperone function of the mutant proteins [32]. Whether the improvement in the chaperone function of small heat shock proteins occurs via modification of a conserved arginine residue and whether physiological levels of MGO could improve the chaperone function through a hydroimidazolone modification is not known. Chaperone function, we replaced R12 with alanine (to mimic the hydroimidazolone modification) and explored the effect of this mutation on the structure and chaperone function of Hsp and aA- and aB-crystallin
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