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

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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)

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.

Suggested Citation

  • Jiao Yang & Yinong Zong & Jiayue Su & Hongtao Li & Huanyu Zhu & Linda Columbus & Lei Zhou & Qinglian Liu, 2017. "Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01310-z
    DOI: 10.1038/s41467-017-01310-z
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