Structural and functional consequences of the cardiomyopathy-associated p.R157C mutation in the C-terminal palindromic motif of human αB-crystallin.

Abstract

αB-crystallin, a small heat shock protein, is crucial for maintaining lenticular transparency and prevents protein aggregation as a molecular chaperone in various tissues. Mutations in αB-crystallin can lead to diseases such as cataracts, cardiomyopathy, and neurodegenerative disorders. This study explores the effects of the p.R157C mutation in the C-terminal domain, near the IXI motif, which is associated with cardiomyopathy. The mutant protein was generated through site-directed mutagenesis, expressed in bacterial systems, and purified by ion-exchange chromatography. Biophysical and computational techniques revealed significant alterations in secondary structure, oligomerization, and conformational stability. The mutation also enhanced chaperone activity and promoted amyloid fibril formation. These alterations may disrupt the interactions of the p.R157C mutant αB-crystallin with cardiac proteins such as desmin and calcineurin, potentially contributing to cardiomyopathy. These findings offer mechanistic insights into αB-crystallin-related cardiomyopathy, shedding light on its pathological role and potential therapeutic targets.