Intrinsic Structural Features of the Human IRE1α Transmembrane Domain Sense Membrane Lipid Saturation

Hyunju Cho; Francesca Stanzione; Amrita Oak; Geun Hyang Kim; Sindura Yerneni; Ling Qi; Amadeu K Sum; Christina Chan

doi:10.1016/j.celrep.2019.03.017

Intrinsic Structural Features of the Human IRE1α Transmembrane Domain Sense Membrane Lipid Saturation

Cell Rep. 2019 Apr 2;27(1):307-320.e5. doi: 10.1016/j.celrep.2019.03.017.

Authors

Hyunju Cho¹, Francesca Stanzione², Amrita Oak³, Geun Hyang Kim⁴, Sindura Yerneni³, Ling Qi⁵, Amadeu K Sum⁶, Christina Chan⁷

Affiliations

¹ Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA; Department of Chemistry, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: hjcho@caltech.edu.
² Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO 80401, USA; Institute of Medical Science-University of Aberdeen, Aberdeen AB25 2ZD, UK.
³ Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA.
⁴ Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
⁵ Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA; Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
⁶ Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO 80401, USA.
⁷ Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: krischan@egr.msu.edu.

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.

Keywords: IRE1α; UPR; dimerization; membrane lipid saturation.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Cells, Cultured
Conserved Sequence
Endoplasmic Reticulum / metabolism
Endoribonucleases / chemistry*
Endoribonucleases / genetics
Endoribonucleases / metabolism
Fatty Acids / metabolism*
Humans
Membrane Lipids / metabolism*
Mice
Mutation
Protein Domains
Protein Multimerization*
Protein Serine-Threonine Kinases / chemistry*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism

Substances

Fatty Acids
Membrane Lipids
ERN1 protein, human
Protein Serine-Threonine Kinases
Endoribonucleases

Abstract

Publication types

MeSH terms

Substances

Grants and funding