The P.K90n Mutation in Human Hspb5 Highlights the Critical Role of Lysine 90 in Chaperone Function and Structural Integrity Publisher Pubmed



Ghaffari AR¹ ; Mirzaei Z¹ ; Shahsavani MB² ; Somee LR¹ ; Stroylova YY³ ; Barinova KV³ ; Amanlou M⁴ ; Muronetz VI³ ; Habibirezaei M⁵ ; Saboury AA⁶ ; Moosavimovahedi AA⁵ ; Yousefi R¹ Show Affiliations
Source: Archives of Biochemistry and Biophysics Published:2025

Abstract

HSPB5 (αB-crystallin), a small heat shock protein, stabilizes proteins and prevents misfolded protein aggregation through dynamic oligomer formation. Mutations in HSPB5 can result in diseases such as myopathy and cataracts. This study focuses on the myopathy-associated p.K90N mutation in the α-crystallin domain and its impact on the structure and function of human HSPB5. The recombinant mutated protein was expressed and purified for analysis using spectroscopy, microscopy, and molecular dynamics simulations. Our results reveal that the p.K90N mutation induces significant structural alterations, including an increase in β-sheet content and a reduction in α-helical structure compared to the wild-type protein. Molecular dynamics simulations showed an increased angle between dimers and decreased accessible surface area in the mutant protein. Additionally, the mutant exhibited a higher propensity for forming larger oligomers and amyloid fibrils, and enhanced thermal stability. These structural changes lead to reduced chaperone activity and impaired protein aggregation prevention, likely contributing to cell death and myopathy. Overall, the p.K90N mutation significantly alters the structural and functional properties of HSPB5, highlighting its pathogenic role and providing insights into disease mechanisms. © 2025 Elsevier Inc.