Auto-regulatory J-domain interactions control Hsp70 recruitment in the oligomeric DNAJB8 co-chaperone.

Bryan D. Ryder, Irina Matlahov, Sofia Bali, Jaime Vaquer-Alicea, Patrick C.A. van der Wel, Lukasz A. Joachimiak

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Received Date: 28th January 20

The Hsp40/Hsp70 chaperone families combine a versatile folding capacity with high specificity, which is mainly facilitated by Hsp40s. The structure and function of many Hsp40s remain poorly understood, with the oligomeric Hsp40s particularly refractory to characterization. Yet, structural insight on the architecture and dynamics of these oligomeric Hsp40s will help explain their potent ability to suppress polyglutamine and other amyloid protein aggregation. Here, our combined in vitro, in vivo, and in silico studies shed new light on the supramolecular structure of the homooligomeric Hsp40 DnaJB8 and how it regulates recruitment of partner Hsp70s. We identify in the oligomers an interaction between the J-Domain (JD) and the beta-sheet-rich C-terminal domain (CTD), causing the sequestration of the JD, and occlusion of its surface necessary for Hsp70 recruitment. We propose a new model for DnaJB8 activity in which a built-in autoinhibitory switch reversibly controls the recruitment of Hsp70. These results provide evidence that the evolutionarily conserved CTD of DnaJB8, and related Hsp40s, serves as an essential regulatory element of their pivotal role in cellular proteostasis.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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