title: An alternative splice variant of human αA-crystallin modulates the oligomer ensemble and the chaperone activity of α-crystallins.
abstract: 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.
authors.affiliation: Department Chemie, Center for Integrated Protein Science, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Preis
authors.affiliation: Department Chemie, Center for Integrated Protein Science, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Bestehorn
authors.affiliation: Department Chemie, Center for Integrated Protein Science, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
authors.affiliation: Department Chemie, Center for Integrated Protein Science, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany. martin.haslbeck@tum.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Haslbeck
mesh_terms: D017398:Alternative Splicing; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics; D038202:alpha-Crystallin A Chain / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D038202:alpha-Crystallin A Chain; D038203:alpha-Crystallin B Chain
keywords: Alpha-crystallin; Alternative splicing; Chaperone function; Protein folding; sHsp