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

Clark, Alice R. and Lubsen, N.H. and Slingsby, Christine (2012) sHSP in the eye lens: crystallin mutations, cataract and proteostasis. The International Journal of Biochemistry & Cell Biology 44 (10), pp. 1687-1697. ISSN 1357-2725.

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Official URL: http://dx.doi.org/10.1016/j.biocel.2012.02.015

Abstract

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 hypothesised to have the α-crystallin “holdase” chaperone function to prevent protein aggregation. We discuss the impact of truncating and missense mutations on α-crystallin, based on recent progress towards determining sHsp 3D structure. Dominant missense mutations to the “α-crystallin domain” of αA- (HSPB4) or αB-crystallin (HSPB5) occur on residues predicted to facilitate domain dynamics. αB-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 β- and γ-crystallins are considered in the context of their possible dependence on the “holdase” chaperone function of α-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 α-crystallin as a chaperone, or as a lens space filler adapted from a chaperone function. Understanding the mechanistic role of α-crystallins will aid progress in research into age-related cataract and adult-onset myopathy.

Item Type: Article
Keyword(s) / Subject(s): crystallin, lens transparency, chaperone, myopathy, small heat shock protein
School or Research Centre: Birkbeck Schools and Research Centres > School of Science > Biological Sciences
Depositing User: Administrator
Date Deposited: 05 Mar 2012 08:36
Last Modified: 17 Apr 2013 12:22
URI: http://eprints.bbk.ac.uk/id/eprint/4616

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