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J Biol Chem. 2011 Sep 2;286(35):30859-66. doi: 10.1074/jbc.M111.273714. Epub 2011 Jul 13.

A conserved structural determinant located at the interdomain region of mammalian inositol-requiring enzyme 1alpha.

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  • 1Graduate Program in Nutrition, Cornell University, Ithaca, New York 14853, USA.

Abstract

Inositol-requiring enzyme 1α (IRE1α), an endoplasmic reticulum-resident sensor for mammalian unfolded protein response, is a bifunctional enzyme containing kinase and RNase domains critical for trans-autophosphorylation and Xbp1 mRNA splicing, respectively, in response to endoplasmic reticulum stress. However, the amino acid residues important for its function and activation remain largely unexplored. Here, through analysis of IRE1α mutants associated with human somatic cancers, we have identified a highly conserved proline residue at position 830 (Pro(830)) that is critical for its structural integrity and hence, the activation of both kinase and RNase domains. Structural analysis revealed that Pro(830) may form a highly conserved structural linker with adjacent tryptophan and tyrosine residues at positions 833 and 945 (Trp(833) and Tyr(945)), thereby bridging the kinase and RNase domains. Indeed, mutation of Pro(830) to leucine (P830L) completely abolished the kinase and RNase activities, significantly decreased protein stability, and prevented oligomerization of IRE1α upon ER stress; similar observations were made for mutations of Trp(833) to alanine (W833A) and to a lesser extent for Y945A. Our finding may facilitate the identification of small molecules to compromise IRE1α function specifically.

PMID:
21757700
[PubMed - indexed for MEDLINE]
PMCID:
PMC3162446
Free PMC Article

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