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Biochemistry - Biophysics - Ophthalmology - Physiology


Hydroimidazolone Modification of the Conserved Arg12 in Small Heat Shock Proteins: Studies on the Structure and Chaperone Function Using Mutant Mimics
Published: Tuesday, January 17, 2012
Author: Ram H. Nagaraj et al.

by Ram H. Nagaraj, Alok Kumar Panda, Shilpa Shanthakumar, Puttur Santhoshkumar, NagaRekha Pasupuleti, Benlian Wang, Ashis Biswas

Methylglyoxal (MGO) is an a-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 aA-crystallin increased its chaperone function. We identified MGO-modified arginine residues in aA-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 aA- and aB-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 aA-crystallin. This enhancement in the chaperone function was accompanied by subtle changes in the tertiary structure, which increased the thermodynamic stability of aA-crystallin. This mutation induced the exposure of additional client protein binding sites on aA-crystallin. Altogether, our data suggest that MGO-modification of the conserved R12 in aA-crystallin to hydroimidazolone may play an important role in reducing protein aggregation in the lens during aging and cataract formation.
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