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.
Highlights
The unfolded protein response is an important cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and carries out a cellular response that attempts to rectify the imbalance
We shed new light on the mechanism of unfolded protein response (UPR) activation by presenting crystal structures of PERK luminal domains captured in two different states
The first dimeric state has been previously described with Ire1 and suggests that both Ire1 and PERK form stable dimers
Summary
The unfolded protein response is an important cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and carries out a cellular response that attempts to rectify the imbalance. These responses include transcriptional up-regulation of UPR target genes, global cell translation attenuation, and activation of ER-associated degradation pathways. There are three sensor/ transducer proteins: Ire, PERK, and Atf, that are critical for initiating mammalian UPR cell signaling and give rise to three separate branches of the response. Crystal structures of yeast and human Ire luminal domains have provided a basis for mechanistic understanding of UPR signal activation, contrasting interpretations of these structures have given rise to differing views on how this occurs (Credle et al, 2005; Zhou et al, 2006; Gardner & Walter, 2011; Walter & Ron, 2011; Korennykh & Walter, 2012; Parmar & Schroder, 2012; Carrara et al, 2013)
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