Regulated structural transitions unleash the chaperone activity of αB-crystallin.
The small heat shock protein αB-crystallin is an oligomeric molecular chaperone that binds aggregation-prone proteins. As a component of the proteostasis system, it is associated with cataract, neurodegenerative diseases, and myopathies. The structural determinants for the regulation of its chaperone function are still largely elusive. Combining different experimental approaches, we show that phosphorylation-induced destabilization of intersubunit interactions mediated by the N-terminal domain (NTD) results in the remodeling of the oligomer ensemble with an increase in smaller, activated species, predominantly 12-mers and 6-mers. Their 3D structures determined by cryo-electron microscopy and biochemical analyses reveal that the NTD in these species gains flexibility and solvent accessibility. These modulated properties are accompanied by an increase in chaperone activity in vivo and in vitro and a more efficient cooperation with the heat shock protein 70 system in client folding. Thus, the modulation of the structural flexibility of the NTD, as described here for phosphorylation, appears to regulate the chaperone activity of αB-crystallin rendering the NTD a conformational sensor for nonnative proteins.
['Peschek|Jirka|J|', 'Braun|Nathalie|N|', 'Rohrberg|Julia|J|', 'Back|Katrin Christiane|KC|', 'Kriehuber|Thomas|T|', 'Kastenmüller|Andreas|A|', 'Weinkauf|Sevil|S|', 'Buchner|Johannes|J|']
D002850:Chromatography, Gel D003001:Cloning, Molecular D020285:Cryoelectron Microscopy D004591:Electrophoresis, Polyacrylamide Gel D018840:HSP70 Heat-Shock Proteins D006367:HeLa Cells D006801:Humans D007091:Image Processing, Computer-Assisted D008958:Models, Molecular D018832:Molecular Chaperones D010766:Phosphorylation D011487:Protein Conformation D012394:Rosaniline Dyes D038203:alpha-Crystallin B Chain
Hsp70 conditional disorder posttranslational modification sHsp structure-function relationship