Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling

Elife. 2015 Feb 18;4:e03522. doi: 10.7554/eLife.03522.

Abstract

The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. How cells detect the accumulation of misfolded proteins remains unclear. In this study, we identify a noncanonical interaction between the ATPase domain of the ER chaperone BiP and the luminal domains of the UPR sensors Ire1 and Perk that dissociates when authentic ER unfolded protein CH1 binds to the canonical substrate binding domain of BiP. Unlike the interaction between chaperone and substrates, we found that the interaction between BiP and UPR sensors was unaffected by nucleotides. Thus, we discover that BiP is dual functional UPR sensor, sensing unfolded proteins by canonical binding to substrates and transducing this event to noncanonical, signaling interaction to Ire1 and Perk. Our observations implicate BiP as the key component for detecting ER stress and suggest an allosteric mechanism for UPR induction.

Keywords: E. coli; ER stress; Ire1; UPR; biochemistry; biophysics; human; perk; structural biology; unfolded protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum Chaperone BiP
  • Endoribonucleases / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Unfolded Protein Response*
  • eIF-2 Kinase / metabolism*

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • EIF2AK3 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases