Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s

Jiao Yang, Yinong Zong, Jiayue Su, Hongtao Li, Huanyu Zhu, Linda Columbus, Lei Zhou and Qinglian Liu ()
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Jiao Yang: Virginia Commonwealth University
Yinong Zong: Virginia Commonwealth University
Jiayue Su: Virginia Commonwealth University
Hongtao Li: Virginia Commonwealth University
Huanyu Zhu: Virginia Commonwealth University
Linda Columbus: University of Virginia
Lei Zhou: Virginia Commonwealth University
Qinglian Liu: Virginia Commonwealth University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Cellular protein homeostasis depends on heat shock proteins 70 kDa (Hsp70s), a class of ubiquitous and highly conserved molecular chaperone. Key to the chaperone activity is an ATP-induced allosteric regulation of polypeptide substrate binding and release. To illuminate the molecular mechanism of this allosteric coupling, here we present a novel crystal structure of an intact human BiP, an essential Hsp70 in ER, in an ATP-bound state. Strikingly, the polypeptide-binding pocket is completely closed, seemingly excluding any substrate binding. Our FRET, biochemical and EPR analysis suggests that this fully closed conformation is the major conformation for the ATP-bound state in solution, providing evidence for an active release of bound polypeptide substrates following ATP binding. The Hsp40 co-chaperone converts this fully closed conformation to an open conformation to initiate productive substrate binding. Taken together, this study provided a mechanistic understanding of the dynamic nature of the polypeptide-binding pocket in the Hsp70 chaperone cycle.

Date: 2017
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DOI: 10.1038/s41467-017-01310-z

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