1. Intrinsic Structural Features of the Human IRE1α Transmembrane Domain Sense Membrane Lipid Saturation.
- Author
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Cho H, Stanzione F, Oak A, Kim GH, Yerneni S, Qi L, Sum AK, and Chan C
- Subjects
- Animals, Cell Line, Cells, Cultured, Conserved Sequence, Endoplasmic Reticulum metabolism, Endoribonucleases genetics, Endoribonucleases metabolism, Humans, Mice, Mutation, Protein Domains, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Endoribonucleases chemistry, Fatty Acids metabolism, Membrane Lipids metabolism, Protein Multimerization, Protein Serine-Threonine Kinases chemistry
- Abstract
Activation of inositol-requiring enzyme (IRE1α) is an indispensable step in remedying the cellular stress associated with lipid perturbation in the endoplasmic reticulum (ER) membrane. IRE1α is a single-spanning ER transmembrane protein possessing both kinase and endonuclease functions, and its activation can be fully achieved through the dimerization and/or oligomerization process. How IRE1α senses membrane lipid saturation remains largely unresolved. Using both computational and experimental tools, we systematically investigated the dimerization process of the transmembrane domain (TMD) of IRE1α and found that, with help of the serine 450 residue, the conserved tryptophan 457 residue buttresses the core dimerization interface of IRE1α-TMD. BiFC (bimolecular fluorescence complementation) experiments revealed that mutation on these residues abolished the saturated fatty acid-induced dimerization in the ER membrane and subsequently inactivated IRE1α activity in vivo. Therefore, our results suggest that the structural elements of IRE1α-TMD serve as a key sensor that detects membrane aberrancy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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