4yzs

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

spinqualitylabelsall models 4yzs, resolution 3.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4yzs is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: W Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [E2AK3_HUMAN] Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function [E2AK3_HUMAN] Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Publication Abstract from PubMed 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 eIF2alpha in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling.,Carrara M, Prischi F, Nowak PR, Ali MM EMBO J. 2015 Apr 28. pii: e201489183. PMID:25925385 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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