The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94

Proc Natl Acad Sci U S A. 2022 Feb 1;119(5):e2118793119. doi: 10.1073/pnas.2118793119.


Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.

Keywords: BiP; Grp94; chaperone; cochaperone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Animals
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Molecular Chaperones / metabolism*
  • Protein Folding


  • Endoplasmic Reticulum Chaperone BiP
  • Membrane Glycoproteins
  • Molecular Chaperones
  • endoplasmin
  • Adenosine Diphosphate