Alpha-crystallin as a molecular chaperone.
The role of alpha-crystallin as a molecular chaperone may explain how the lens stays transparent for so long. Alpha-crystallin prevents the aggregation of other lens crystallins and proteins that have become unfolded by "trapping" the protein in a high molecular weight complex. It also protects enzyme activities. The substrate protein may interact while in a molten globule state. Alpha-crystallin predominantly binds to proteins very early in the denaturation pathways. The amphiphilic nature of alpha-crystallin, a polar C-terminal-region and a hydrophobic N-terminal-region are all essential for chaperone function. The flexible C-terminal extension maintains solubility and can bind to opposing charged residues of unfolding proteins. Hydrophobic regions in the N-terminal region then hold the unfolded protein. Specific areas important for chaperone binding and function have been identified throughout the N-terminal-region, connecting peptide and C-terminal extension. After a substantial amount of chemical data and models, cryo-EM images of alpha-crystallin have confirmed a variable 3D surface with a hollow interior. Alpha-crystallin taken from the lens nucleus shows an age-dependent decrease in chaperone function. High molecular weight aggregates and alpha-crystallin found within the nucleus from clear and cataract lenses have reduced chaperone function. Post-translational modifications, known to occur during ageing, such as glycation, carbamylation, oxidation, phosphorylation and truncation cause a decrease in chaperone function. Alpha-crystallin is expressed outside the lens. AlphaB-crystallin can be induced by heat shock in many tissues where it is translocated from cytoplasm to nucleus. Increased expression of alphaB-crystallin has been seen in many pathological states. Conformational disorders, including cataract may have a common aetiology and potentially a common therapy.
Derham
B K
BK
Nuffield Laboratory of Ophthalmology, University of Oxford, UK.
Harding
J J
JJ
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003459:Crystallins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D003459:Crystallins; D018832:Molecular Chaperones