6shc
Crystal structure of human IRE1 luminal domain Q105CCrystal structure of human IRE1 luminal domain Q105C
Structural highlights
FunctionERN1_HUMAN Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.[1] [2] [3] [UniProtKB:Q9EQY0] Publication Abstract from PubMedCoupling of endoplasmic reticulum stress to dimerisationdependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1's stress-sensing luminal domain (IRE1(LD)) that favours the latter's monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1alpha repressed UPR signalling in CHO cells and deletions in the IRE1alpha locus that de-repressed the UPR in cells, encode flexible regions of IRE1(LD) that mediated BiPinduced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1(LD) induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1(LD) dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1(LD) to initiate active repression of UPR signalling. Unstructured regions in IRE1alpha specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR.,Amin-Wetzel N, Neidhardt L, Yan Y, Mayer MP, Ron D Elife. 2019 Dec 24;8. pii: 50793. doi: 10.7554/eLife.50793. PMID:31873072[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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