An alternative splice variant of human [alpha]A-crystallin modulates the oligomer ensemble and the chaperone activity of [alpha]-crystallins

• Published in: Cell stress & chaperones Vol. 22; no. 4; p. 541
• Main Authors: Preis, Waldemar, Bestehorn, Annika, Buchner, Johannes, Haslbeck, Martin
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Nature B.V 01-07-2017
• Subjects: Acuity; Agglomeration; Alternative splicing; Amino acids; Crystal structure; Crystallin; Displays; Eye; Eye lens; Genes; Heat; Heat exchange; Heat shock proteins; Isoforms; Lenses; Molecular structure; mRNA; Oligomers; Protein interaction; Protein structure; Proteins; Secondary structure; Small heat shock proteins; Transcription; Visual acuity
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-017-0772-2

In humans, ten genes encode small heat shock proteins with lens [alpha]A-crystallin and [alpha]B-crystallin representing two of the most prominent members. The canonical isoforms of [alpha]A-crystallin and [alpha]B-crystallin collaborate in the eye lens to prevent irreversible protein aggregation and preserve visual acuity. [alpha]-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 [alpha]A-crystallin with an exchanged N-terminal sequence. This variant shows the characteristic [alpha]-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 [alpha]A-crystallin and [alpha]B-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 [alpha]A-crystallin leads to an additional, formerly not characterized [alpha]A-crystallin species which is able to modulate the properties of the canonical ensemble of [alpha]-crystallin oligomers.