Activation of the Unfolded Protein Response by Lipid Bilayer Stress.
The unfolded protein response (UPR) is a conserved homeostatic program that is activated by misfolded proteins in the lumen of the endoplasmic reticulum (ER). Recently, it became evident that aberrant lipid compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent in activating the UPR. The underlying molecular mechanism, ... however, remained unclear. We show that the most conserved transducer of ER stress, Ire1, uses an amphipathic helix (AH) to sense membrane aberrancies and control UPR activity. In vivo and in vitro experiments, together with molecular dynamics (MD) simulations, identify the physicochemical properties of the membrane environment that control Ire1 oligomerization. This work establishes the molecular mechanism of UPR activation by lipid bilayer stress.
Mesh Terms:
Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Intracellular Membranes, Lipid Bilayers, Membrane Glycoproteins, Molecular Dynamics Simulation, Mutation, Protein Conformation, alpha-Helical, Protein Folding, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Structure-Activity Relationship, Time Factors, Unfolded Protein Response
Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Intracellular Membranes, Lipid Bilayers, Membrane Glycoproteins, Molecular Dynamics Simulation, Mutation, Protein Conformation, alpha-Helical, Protein Folding, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Structure-Activity Relationship, Time Factors, Unfolded Protein Response
Mol. Cell
Date: Aug. 17, 2017
PubMed ID: 28689662
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