The congenital cataract-linked A2V mutation impairs tetramer formation and promotes aggregation of ?B2-crystallin.

ABSTRACT: ?/?-Crystallins, the major structural proteins in human lens, are highly conserved in their tertiary structures but distinct in the quaternary structures. The N- and C-terminal extensions have been proposed to play a crucial role in mediating the size of ?-crystallin assembly. In this research, we investigated the molecular mechanism underlying the congenital hereditary cataract caused by the recently characterized A2V mutation in ?B2-crystallin. Spectroscopic experiments indicated that the mutation did not affect the secondary and tertiary structures of ?B2-crystallin. The mutation did not affect the formation of ?B2/?A3-crystallin heteromer as well as the stability and folding of the heteromer, suggesting that the mutation might not interfere with the protein interacting network in the lens. However, the tetramerization of ?B2-crystallin at high protein concentrations was retarded by the A2V mutation. The mutation slightly decreased the thermal stability and promoted the thermal aggregation of ?B2-crystallin. Although it did not influence the stability of ?B2-crystallin against denaturation induced by chemical denaturants and UV irradiation, the A2V mutant was more prone to be trapped in the off-pathway aggregation process during kinetic refolding. Our results suggested that the A2V mutation might lead to injury of lens optical properties by decreasing ?B2-crystallin stability against heat treatment and by impairing ?B2-crystallin assembly into high-order homo-oligomers.

SUBMITTER: Xu J 

PROVIDER: S-EPMC3516508 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature