UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor
File(s)
Accepted version
Author(s)
Kopp, Megan C
Larburu, Natacha
vinoth, Durairaj
Adams, Christopher J
Ali, Maruf MU
Type
Journal Article
Abstract
BiP is a major ER chaperone and suggested to act as primary sensor in the activation
of the unfolded protein response (UPR). How BiP operates as a molecular chaperone
and as an ER stress sensor is unknown. Here, by reconstituting components of
human UPR, ER stress and BiP chaperone systems, we discover that the interaction
of BiP with the luminal domains (LD) of UPR proteins, IRE1 and PERK, switch BiP
from its chaperone cycle into an ER stress sensor cycle by preventing the binding of
its cochaperones, with loss of ATPase stimulation. Furthermore, misfolded proteindependent
dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data
elucidate a previously unidentified mechanistic cycle of BiP function that explains its
ability to act as a Hsp70 chaperone and ER stress sensor.
of the unfolded protein response (UPR). How BiP operates as a molecular chaperone
and as an ER stress sensor is unknown. Here, by reconstituting components of
human UPR, ER stress and BiP chaperone systems, we discover that the interaction
of BiP with the luminal domains (LD) of UPR proteins, IRE1 and PERK, switch BiP
from its chaperone cycle into an ER stress sensor cycle by preventing the binding of
its cochaperones, with loss of ATPase stimulation. Furthermore, misfolded proteindependent
dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data
elucidate a previously unidentified mechanistic cycle of BiP function that explains its
ability to act as a Hsp70 chaperone and ER stress sensor.
Date Issued
2019-11-06
Date Acceptance
2019-10-01
Citation
Nature Structural and Molecular Biology, 2019, 26, pp.1053-1062
ISSN
1545-9985
Publisher
Nature Research
Start Page
1053
End Page
1062
Journal / Book Title
Nature Structural and Molecular Biology
Volume
26
Copyright Statement
© 2019 Springer Nature Limited
Sponsor
Cancer Research UK
Cancer Research UK
Grant Number
20752
23215
Subjects
11 Medical and Health Sciences
03 Chemical Sciences
06 Biological Sciences
Biophysics
Developmental Biology
Publication Status
Published