Structure and function of small heat shock/α-crystallin proteins: established concepts and emerging ideas

Abstract

Small heat shock/alpha-crystallin proteins are defined by conserved sequence of approximately 90 amino acid residues, termed the alpha-crystallin domain, which is bounded by variable amino- and carboxy-terminal extensions. These proteins form oligomers, most of uncertain quaternary structure, and oligomerization is prerequisite to their function as molecular chaperones. Sequence modelling and physical analyses show that the secondary structure of small heat shock/alpha-crystallin proteins is predominately beta-pleated sheet. Crystallography, site-directed spin-labelling and yeast two-hybrid selection demonstrate regions of secondary structure within the alpha-crystallin domain that interact during oligomer assembly, a process also dependent on the amino terminus. Oligomers are dynamic, exhibiting subunit exchange and organizational plasticity, perhaps leading to functional diversity. Exposure of hydrophobic residues by structural modification facilitates chaperoning where denaturing proteins in the molten globule state associate with oligomers. The flexible carboxy-terminal extension contributes to chaperone activity by enhancing the solubility of small heat shock/alpha-crystallin proteins. Site-directed mutagenesis has yielded proteins where the effect of the change on structure and function depends upon the residue modified, the organism under study and the analytical techniques used. Most revealing, substitution of a conserved arginine residue within the alpha-crystallin domain has a major impact on quaternary structure and chaperone action probably through realignment of beta-sheets. These mutations are linked to inherited diseases. Oligomer size is regulated by a stress-responsive cascade including MAPKAP kinase 2/3 and p38. Phosphorylation of small heat shock/alpha-crystallin proteins has important consequences within stressed cells, especially for microfilaments.

Insulin-induced myocardial protection in isolated ischemic rat hearts requires p38 MAPK phosphorylation of Hsp27

“…Thirty minutes of ischemia causes substantial cellular injury in control hearts as indicated by release of creatine kinase and disruption of mitochondria (13,34) particularly with reperfusion. Improved myocardial function after ischemia is associated with minimal release of creatine kinase and maintenance of cellular morphology, and such protection has been repeatedly associated with elevated expression of Hsp70 (13,34,46,59). However, in the current study, the improved myocardial function is unlikely to be due to elevated levels of Hsp70 or Hsp27.…”

“…In general, Hsps, acting as molecular chaperones, regulate folding of nascent proteins; participate in refolding or the renaturation of misfolded, damaged, or denatured proteins; stabilize structural proteins; and facilitate the translocation of proteins across membranes among cellular compartments (30,46). Several Hsps prevent aggregation of protein and target unstable or damaged protein for degradation.…”

Chemical Signals of Vector Beetle Facilitate the Prevalence of a Native Fungus and the Invasive Pinewood Nematode

“…The sHSP as a family of molecular chaperones are characterized by low molecular mass of 12 to 23 kDa (MacRae, 2000), possession of a conserved a-crystallin domain, and formation of large oligomers (Cobb and Petrash, 2000;Haslbeck et al, 2005;Sun and MacRae, 2005). Among the molecular chaperone families, sHSP are the only known ATP-independent chaperones ( Jakob et al, 1993) and act as ''holdase'' for partially folded intermediates under stress conditions, which can be released and refolded at optimal conditions with the help of ATP-dependent chaperones (Wang and Spector, 2000;Cashikar et al, 2005).…”

Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy

“…HSPB8 belongs to the superfamily of mammalian small heat-shock proteins or stress proteins [13][14][15][16] . Members of this superfamily share a conserved α-crystallin domain in their C-terminal part and the WDPF motif in their N-terminal part, whereas other parts of the sequence (N-terminal halves and extreme C-terminal tails) are more variable 17,18 . The missense mutations K141N and K141E are located in the central α-crystallin domain of HSPB8.…”