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Publication Abstract from PubMed

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.

Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s.,Yang J, Zong Y, Su J, Li H, Zhu H, Columbus L, Zhou L, Liu Q Nat Commun. 2017 Oct 31;8(1):1201. doi: 10.1038/s41467-017-01310-z. PMID:29084938^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.