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Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling

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Title: Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling
Authors: Carrara, M
Prischi, F
Nowak, P
Ali, M
Item Type: Journal Article
Abstract: Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein‐folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X‐ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation.
Issue Date: 29-Apr-2015
Date of Acceptance: 13-Apr-2015
URI: http://hdl.handle.net/10044/1/23551
DOI: 10.15252/embj.201489183
ISSN: 0261-4189
Publisher: EMBO Press
Start Page: 1589
End Page: 1600
Journal / Book Title: EMBO Journal
Volume: 34
Copyright Statement: © 2015 The Authors. License: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Cancer Research UK
Medical Research Council (MRC)
Funder's Grant Number: 11161
MR/L007436/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
cell signaling
ER stress
PERK
unfolded protein response
UNFOLDED PROTEIN RESPONSE
IRE1
DIMERIZATION
KINASE
OLIGOMERIZATION
ACTIVATION
PHOSPHORYLATION
PATHWAY
INDUCE
ER stress
PERK
cell signaling
unfolded protein response
Animals
Cells, Cultured
Crystallography, X-Ray
Endoplasmic Reticulum Stress
Eukaryotic Initiation Factor-2
Humans
Mice
Mice, Knockout
Phosphorylation
Protein Multimerization
Protein Structure, Quaternary
Protein Structure, Tertiary
Signal Transduction
Unfolded Protein Response
eIF-2 Kinase
Cells, Cultured
Animals
Mice, Knockout
Humans
Mice
eIF-2 Kinase
Eukaryotic Initiation Factor-2
Crystallography, X-Ray
Signal Transduction
Protein Structure, Quaternary
Protein Structure, Tertiary
Phosphorylation
Protein Multimerization
Unfolded Protein Response
Endoplasmic Reticulum Stress
06 Biological Sciences
08 Information and Computing Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status: Published
Online Publication Date: 2015-04-29
Appears in Collections:Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons