Intrinsic Structural Features of the Human IRE1? Transmembrane Domain Sense Membrane Lipid Saturation.

ABSTRACT: Activation of inositol-requiring enzyme (IRE1?) is an indispensable step in remedying the cellular stress associated with lipid perturbation in the endoplasmic reticulum (ER) membrane. IRE1? 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 IRE1? 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 IRE1? and found that, with help of the serine 450 residue, the conserved tryptophan 457 residue buttresses the core dimerization interface of IRE1?-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 IRE1? activity in vivo. Therefore, our results suggest that the structural elements of IRE1?-TMD serve as a key sensor that detects membrane aberrancy.

SUBMITTER: Cho H 

PROVIDER: S-EPMC6467502 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature