HSPB5

HSPB5, also known as alpha-B-crystallin (CRYAB), is a member of the small heat shock protein (sHSP) family. The encoded protein acts as a molecular chaperone preventing aggregation of misfolded proteins, especially under cellular stress, and is highly expressed in skeletal and cardiac muscle with notable levels in the brain and lens.

It is a ~20 kDa protein that forms dynamic oligomers regulated by phosphorylation. A conserved alpha-crystallin domain is flanked by flexible N- and C-terminal regions crucial for oligomer assembly and client interactions.

As an ATP-independent chaperone, HSPB5 binds exposed hydrophobic regions on unfolded proteins and helps stabilize cytoskeletal elements such as desmin, contributing to sarcomere integrity. It also participates in anti-apoptotic pathways, aiding cell survival during stress, and phosphorylation can alter oligomer size and chaperone activity.

Regulation occurs through phosphorylation at Ser19, Ser45, and Ser59 by stress-activated kinases, modulating chaperone function in response to heat, oxidative stress, and exercise. Its expression can be upregulated in response to cellular stress, aging, or cardiac disease.

Clinically, mutations in HSPB5/CRYAB cause inherited myopathies and cardiomyopathies, sometimes with cataracts. The R120G variant is well studied and linked to desmin-related myopathy and familial cardiomyopathy; other mutations produce variable phenotypes with autosomal dominant inheritance. The protein’s lens expression also implicates CRYAB abnormalities in cataract formation, illustrating its diverse roles in muscle, heart, and eye tissues.