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Structural basis for client recognition and activity of Hsp40 chaperones

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Science  20 Sep 2019:
Vol. 365, Issue 6459, pp. 1313-1319
DOI: 10.1126/science.aax1280

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Catch and release

Chaperones are essential for proper protein folding inside cells, but their interactions with client proteins are difficult to study because they are dynamic. Jiang et al. used nuclear magnetic resonance spectroscopy to look at how the chaperones Hsp70 and Hsp40 work together in the client binding and release cycle. Hsp40 alters the folding properties of the client protein, perhaps unfolding a non-native state, by binding dynamically through multiple binding sites. Hsp70 binding to Hsp40 displaces the unfolded client. The released protein may either fold to its native state, or be rebound for another chaperone cycle.

Science, this issue p. 1313

Abstract

Hsp70 and Hsp40 chaperones work synergistically in a wide range of biological processes including protein synthesis, membrane translocation, and folding. We used nuclear magnetic resonance spectroscopy to determine the solution structure and dynamic features of an Hsp40 in complex with an unfolded client protein. Atomic structures of the various binding sites in the client complexed to the binding domains of the Hsp40 reveal the recognition pattern. Hsp40 engages the client in a highly dynamic fashion using a multivalent binding mechanism that alters the folding properties of the client. Different Hsp40 family members have different numbers of client-binding sites with distinct sequence selectivity, providing additional mechanisms for activity regulation and function modification. Hsp70 binding to Hsp40 displaces the unfolded client. The activity of Hsp40 is altered in its complex with Hsp70, further regulating client binding and release.

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