Molecular mechanism of the luminal dimerization domain of human IRE1 in unfolded protein response pathway

Abstract

The endoplasmic reticulum (ER) is a major compartment for protein folding and protein maturation in eukaryotic cells. Perturbations in the extra-cellular environment can lead to accumulation of unfolded proteins in ER, which will have potentially deleterious effects on the living cells. A class of novel ER trans-membrane receptors including IRE1, PERK, and ATF6 was activated in an intracellular signal transduction pathway termed the unfolded protein response (UPR) to up-regulate the protein-folding capacity or down-regulate the protein synthesis rate to release the ER stress. All three proteins may use a common sensing mechanism for its activation: releasing of the inhibitory ER chaperone BiP. Here we present the crystal structure of the N-terminal luminal domain (NLD) of human IRE1α. Biochemical studies show that disruption of dimerization of the human IRE1α NLD can cause severe deficiency of its activation in the UPR pathway.