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Nat Commun. 2017 Oct 31;8(1):1201. doi: 10.1038/s41467-017-01310-z.

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

Author information

1
Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
2
Department of Chemistry, University of Virginia, Charlottesville, VA, 22908, USA.
3
Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298, USA. qinglian.liu@vcuhealth.org.

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.

PMID:
29084938
PMCID:
PMC5662698
DOI:
10.1038/s41467-017-01310-z
[Indexed for MEDLINE]
Free PMC Article

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