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RNase domain (also known as the kinase extension nuclease domain) of Ire1 The model represents the C-terminal endoribonuclease domain of the multi-functional protein Ire1; Ire1 in addition contains a type I transmembrane serine/threonine protein kinase (STK) domain, and a Luminal dimerization domain. Ire1 is essential for the endoplasmic reticulum (ER) unfolded protein response (UPR), which acts as an ER stress sensor and is the oldest and most conserved component of the UPR in eukaryotes. During ER stress, IRE1 dimerizes through its N-terminal luminal domain and forms oligomers, promoting trans-autophosphorylation by its cytosolic kinase domain. This leads to a conformational change that stimulates its endoribonuclease (RNase) activity and results in the cleavage of its mRNA substrate, Hac1 in yeast and Xbp1 in metazoans, thus promoting a splicing event that enables translation into a transcription factor which activates the UPR. This RNase domain is homologous to the RNase domain of RNase L, and possesses a novel fold for a nuclease and appears to be rigid irrespective of the activation state of IRE1. Structural analysis and mutational studies have revealed that an early stage 'phosphoryl-transfer' competent conformation of IRE1 favors face-to-face dimerization of the kinase domains which precedes and is distinct from the RNase 'active' back-to-back conformation. Furthermore, in yeast IRE1, the flavonol quercetin activates the RNase and potentiates activation of the protein kinase by ADP, hinting at the possible existence of endogenous cytoplasmic ligands that may function along with stress signals from ER lumen in order to modulate IRE1 activity, thus identifying IRE1 as a target for development of ATP-competitive inhibitors to modulate the UPR with specific relevance for multiple myeloma. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",