Structural Insights into IRE1 Functions in the Unfolded Protein Response

IRE1 signaling is the most evolutionarily conserved branch in the UPR. IRE1 is an ER stress sensor and provides a structure-based platform for the unfolded proteins docking, which causes the luminal domain conformational change and oligomerization. This selfassociation of IRE1 facilitates the phosphorylation of activation loop, which unlocks the autoinhibition in the kinase domain. The activating mechanistic cascade is thus initiated to induce DFG-in conformational change and movement of αC-helix to the active site. Structurally, RNase activity is coupled to autophosphorylation and activation of kinase domain. Consequently, the activation of RNase domain in human IRE1 indicates the conformational rearrangement switching the structural arranging pattern from face-to-face to back-to-back. IRE1 is still under investigation for target-specific drug development. Two types of ATP-competitive inhibitors of IRE1 kinase are introduced to modify RNase activity, regulating the UPR in response to ER stress. However, once the high activation of RNase surpasses the threshold, its biological roles will switch from adaption to destruction. This might explain for the dual functions of IRE1 in pro-survival and pro-apoptosis. Structural and mechanistic studies of IRE1 highlight the challenge of controlling the UPR in diseases. Keywords: IRE1, kinase domain, RNase domain, activation loop, αC-helix, conformational change.