ER-stress sensing mechanism of the unfolded protein response sensor/transducer IRE1 is conserved from yeast to mammals, where in mammals, unfolded protein binding to IRE1's ER lumenal domain is coupled to its oligomerization and activation through an allosteric conformational change.
Client protein-driven reversal of endoplasmic reticulum chaperone (BiP) mediated-repression is revealed as a principal component of the regulation of the unfolded protein response transducer IRE1 in cells.
Quantitative FRET UPR induction assay is used to measure IRE1 and BIP association and dissociation by a variety of ER misfolded proteins and by an important BiP substrate-binding domain mutant, significantly enhancing the evidence for the allosteric UPR induction model.
Biochemical analysis and computational modeling reveal how cells mechanistically control the quality of their proteomes and demonstrate that the precise alignment of subunits in oligomeric complexes can profoundly affect enzymatic properties.
A rationally designed small molecule ATP-mimetic activates IRE1 and PERK signaling in cells by inducing conformational changes that template the assembly of higher-order enzymatically active structures.