CRYAB

CRYAB (alpha-crystallin B chain, also known as HSPB5) is a small heat shock protein that functions as a molecular chaperone with holdase activity. It binds partially denatured or destabilized proteins in an ATP-independent manner to prevent their aggregation, but unlike HSP70-family foldase chaperones, it does NOT actively refold substrates. CRYAB forms large polydisperse oligomeric complexes, typically of 10-40 subunits, and can hetero-oligomerize with CRYAA (HSPB4). The canonical sHSP architecture comprises a central alpha-crystallin domain (ACD) flanked by a variable N-terminal domain (NTD) and a short C-terminal domain (CTD); chaperone activity is tightly coupled to oligomeric assembly and dynamic subunit exchange (DOI:10.1038/s41467-024-54647-7). A conserved N-terminal IXI-like motif (NT-IXI) engages the ACD hydrophobic groove, and perturbation of this motif transforms native assemblies into reversible elongated helical fibrils, as resolved by cryo-EM (DOI:10.1038/s41467-024-54647-7). Stress-activated phosphorylation at Ser19/Ser45/Ser59 by p38 MAPK modulates oligomeric state; the p38-CRYAB(pS59) cascade is a stress-response module that can shift CRYAB condensates toward less dynamic, aggregate-prone states under pathological conditions (DOI:10.1016/j.isci.2024.109510, DOI:10.1172/jci163730). In the eye lens, CRYAB serves dual roles as a structural protein contributing to transparency and refractive index, and as a chaperone preventing aggregation of damaged crystallins. Outside the lens, it is highly expressed in cardiac and skeletal muscle where it associates with cytoskeletal elements including desmin intermediate filaments and titin at Z-bands and intercalated disks. CRYAB also functions as a mitochondrial chaperone and anti-apoptotic protein, binding pro-apoptotic factors Bax, Bcl-X(S), cytochrome c, and VDAC; the E105K mutation causing hereditary optic atrophy reduces these interactions and impairs mitochondrial OXPHOS assembly (DOI:10.1172/jci.insight.182209). CRYAB is secreted via extracellular vesicles and exerts paracrine effects including promotion of angiogenesis in cardiac contexts (DOI:10.1186/s13287-023-03468-4, DOI:10.1038/s42003-022-04402-9). Mutations in CRYAB cause myofibrillar myopathy, cataracts, dilated cardiomyopathy, restrictive cardiomyopathy, and hereditary optic atrophy.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.