Abstract
Molecular chaperones facilitate and regulate protein conformational change within cells. This encompasses many fundamental cellular processes: including the correct folding of nascent chains; protein transport and translocation; signal transduction and protein quality control. Chaperones are, therefore, important in several forms of human disease, including neurodegeneration. Within the retina, the highly specialized photoreceptor cell presents a fascinating paradigm to investigate the specialization of molecular chaperone function and reveals unique chaperone requirements essential to photoreceptor function. Mutations in several photoreceptor proteins lead to protein misfolding mediated neurodegeneration. The best characterized of these are mutations in the molecular light sensor, rhodopsin, which cause autosomal dominant retinitis pigmentosa. Rhodopsin biogenesis is likely to require chaperones, while rhodopsin misfolding involves molecular chaperones in quality control and the cellular response to protein aggregation. Furthermore, the specialization of components of the chaperone machinery to photoreceptor specific roles has been revealed by the identification of mutations in molecular chaperones that cause inherited retinal dysfunction and degeneration. These chaperones are involved in several important cellular pathways and further illuminate the essential and diverse roles of molecular chaperones.
Highlights
The retina is rich in chaperones and several could be involved in rod opsin biogenesis or the response to rod opsin misfolding
The full significance of the interaction of HSJ1 proteins with rod opsin remains to be determined; it is clear that the retina has specialized chaperones that are essential for normal vision
In contrast to BBS6 and BBS12, the functional motif for ATP hydrolysis is conserved in BBS10, suggesting that BBS10 might function as an active enzyme (Stoetzel et al, 2006)
Summary
Molecular chaperones are facilitators and regulators of protein conformational change (Ellis and Hartl, 1999). The best-studied and mechanistically understood chaperone machines are Hsp and Hsp families These chaperones recognize and interact with unfolded or partially folded polypeptides by binding to exposed hydrophobic regions within proteins preventing them from aggregating and maintaining them in a folding competent state until release. Hsp (chaperonins) facilitate folding by enclosing non-native polypeptides in the central cavity (or ‘cage’) of a ring structure formed from identical or closely related rotationally symmetrical subunits (Rye et al, 1999) Another example of chaperone activity is the peptidyl– prolyl cis–trans isomerase (PPIase) activity found in the cyclophilins (e.g. NinaA) that overcomes a rate limiting step in protein folding, the correct orientation of proline residues (Yaffe et al, 1997; Andreotti, 2003). The following is a brief description of the properties of these families
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