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

Small heat shock/alpha-crystallin proteins are defined by a conserved seque nce of approximately 90 amino acid residues, termed the alpha-crystallin do main, 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-cryst allin domain that interact during oligomer assembly, a process also depende nt on the amino terminus. Oligomers are dynamic, exhibiting subunit exchang e and organizational plasticity, perhaps leading to functional diversity. E xposure of hydrophobic residues by structural modification facilitates chap eroning, where denaturing proteins in the molten globule state associate wi th oligomers. The flexible carboxy-terminal extension contributes to chaper one activity by enhancing the solubility of small heat shock/alpha-crystall in proteins. Site-directed mutagenesis has yielded proteins where the effec t of the change on structure and function depends upon the residue modified , the organism under study and the analytical techniques used. Most reveali ng, substitution of a conserved arginine residue within the alpha-crystalli n domain has a major impact on quaternary structure and chaperone action, p robably through realignment of beta-sheets. These mutations are linked to i nherited diseases. Oligomer size is regulated by a stress-responsive cascad e including MAPKAP kinase 2/3 and p38. Phosphorylation of small heat shock/ alpha-crystallin proteins has important consequences within stressed cells, especially for microfilaments.