sHSP in the eye lens: Crystallin mutations, cataract and proteostasis

alpha-Crystallin, a major component of the eye lens cytoplasm, is a large multimer formed from two members of the small heat shock protein (sHsp) family. Inherited crystallin mutations are a common cause of childhood cataract, whereas miscellaneous changes to the long-lived crystallins cause age-related cataract, the most common cause of blindness worldwide. Newly formed eye lens cells use proteostasis to deal with the consequences of mutations, whereas mature lens cells, devoid of the ATP-driven folding and degradation machines, are hypothesized to have the alpha-crystallin holdase chaperone function to prevent protein aggregation. We discuss the impact of truncating and missense mutations on alpha-crystallin, based on recent progress towards determining sHsp 3D structure. Dominant missense mutations to the alpha-crystallin domain of alpha A- (HSPB4) or alpha B-crystallin (HSPB5) occur on residues predicted to facilitate domain dynamics. alpha B-Crystallin is also expressed in striated muscle and mutations cause myopathy. The impact on these cellular cytoplasms is compared where sHsp multimer partners and metabolic constraints are different. Selected inherited mutations of the lens beta- and gamma-crystallins are considered in the context of their possible dependence on the holdase chaperone function of alpha-crystallin. Looking at discrete changes to specific crystallin polypeptide chains that can function as chaperone or substrate provide insights into the workings of a cytoplasmic proteostatic system. These observations provide a framework for validating the function of alpha-crystallin as a chaperone, or as a lens space filler adapted from a chaperone function. Understanding the mechanistic role of alpha-crystallins will aid progress in research into age-related cataract and adult-onset myopathy. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.