Journal Article

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

Nowak, Piotr R, Kopp, Megan C, Ali, Maruf MU, Prischi, Filippo, Carrara, Marta

2015

Overview

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. Proteins perform many essential tasks in cells, but to be able to work they first have to correctly fold into a specific three-dimensional shape. Within the cell, many proteins are folded with the help of ‘chaperone’ proteins. If any proteins fold incorrectly, the normal workings of the cell can be disturbed, which may damage the cell. This is more likely to happen if a cell suddenly requires a large number of proteins to be made, which can overwhelm the chaperone proteins. In humans and other eukaryotic organisms, many proteins are folded in a compartment within the cell called the endoplasmic reticulum. Inside this compartment there is a system called the unfolded protein response that detects misfolded proteins and boosts the cell's capacity to re-fold them. As part of this system, two sensor proteins detect when misfolded proteins are present, but it is not clear how they do so. It has been suggested that a chaperone protein called BiP may be able to activate these sensor proteins in order to turn on the unfolded protein response. In this study, Carrara et al. studied the sensor proteins and BiP using an artificial set-up in the laboratory. The experiments show that both of the sensor proteins can bind to a section of the BiP chaperone called the ATPase domain. However, in the presence of an unfolded protein, BiP stopped interacting with the sensor proteins, which could allow the sensor proteins to activate the unfolded protein response. The experiments also show that BiP must bind to the unfolded protein to activate the unfolded protein response. Carrara et al.'s findings suggest that BiP has a dual role in cells: to sense unfolded proteins by binding to them, and then to activate the sensor proteins that trigger the unfolded protein response. Together, these results suggest a new model for how cells detect and respond to misfolded proteins within the endoplasmic reticulum, and may provide new targets for therapies to treat diseases caused by defects in protein folding.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adenosine triphosphatase / Allosteric properties / Biochemistry / Biophysics and Structural Biology / eIF-2 Kinase - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum Chaperone BiP / Endoribonucleases - metabolism / ER stress / Heat-Shock Proteins - metabolism / Homeostasis / Humans / Ire1 / Nucleotides / perk / Protein Binding / Protein folding / Protein Serine-Threonine Kinases - metabolism / Proteins / unfolded protein / Unfolded Protein Response / UPR