An alternative splice variant of human αA-crystallin modulates the oligomer ensemble and the chaperone activity of α-crystallins
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In humans, ten genes encode small heat shock proteins with lens αA-crystallin and αB-crystallin representing two of the most prominent members. The canonical isoforms of αA-crystallin and αB-crystallin collaborate in the eye lens to prevent irreversible protein aggregation and preserve visual acuity. α-Crystallins form large polydisperse homo-oligomers and hetero-oligomers and as part of the proteostasis system bind substrate proteins in non-native conformations, thereby stabilizing them. Here, we analyzed a previously uncharacterized, alternative splice variant (isoform 2) of human αA-crystallin with an exchanged N-terminal sequence. This variant shows the characteristic α-crystallin secondary structure, exists on its own predominantly in a monomer–dimer equilibrium, and displays only low chaperone activity. However, the variant is able to integrate into higher order oligomers of canonical αA-crystallin and αB-crystallin as well as their hetero-oligomer. The presence of the variant leads to the formation of new types of higher order hetero-oligomers with an overall decreased number of subunits and enhanced chaperone activity. Thus, alternative mRNA splicing of human αA-crystallin leads to an additional, formerly not characterized αA-crystallin species which is able to modulate the properties of the canonical ensemble of α-crystallin oligomers.
KeywordsAlpha-crystallin Alternative splicing Protein folding Chaperone function sHsp
We thank Gina Feind for excellent experimental assistance, Robert Pesch and Ralf Zimmer for discussion of bioinformatics data on alternative splicing, and Evgeny Mymrikov for αB-crystallin. The Deutsche Forschungsgemeinschaft (SFB 1035) and CIPSM are acknowledged for financial support.
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