4YZS

Crystal structures reveal transient PERK luminal domain tetramerization in ER stress signaling

Summary for 4YZS

• Entry DOI: 10.2210/pdb4yzs/pdb
• Descriptor: Eukaryotic translation initiation factor 2-alpha kinase 3, TUNGSTEN ION (2 entities in total)
• Functional Keywords: perk, upr, er stress, tetramer, upr activation, upr sensor, unfolded protein, proteostasis, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane; Single-pass type I membrane protein: Q9NZJ5
• Total number of polymer chains: 2
• Total formula weight: 68600.11

Authors

Carrara, M.,Prischi, F.,Ali, M.M.U. (deposition date: 2015-03-25, release date: 2015-05-13, Last modification date: 2024-11-20)

Primary citation

Carrara, M.,Prischi, F.,Nowak, P.R.,Ali, M.M.
Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling.
Embo J., 34:1589-1600, 2015

PubMed 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.

PubMed: 25925385
DOI: 10.15252/embj.201489183

Experimental method

X-RAY DIFFRACTION (3.14 Å)