A Eukaryotic Sensor for Membrane Lipid Saturation

• Published in: Molecular cell 2016-07, Vol.63 (1), p.49-59
• Main Authors: Covino, Roberto, Ballweg, Stephanie, Stordeur, Claudius, Michaelis, Jonas B., Puth, Kristina, Wernig, Florian, Bahrami, Amir, Ernst, Andreas M., Hummer, Gerhard, Ernst, Robert
• Format: Article
• Language: English
• Subjects: Electron Spin Resonance Spectroscopy; Endoplasmic Reticulum - metabolism; Fatty Acid Desaturases - genetics; Fatty Acid Desaturases - metabolism; Fatty Acids - metabolism; Gene Expression Regulation, Fungal; Intracellular Membranes - metabolism; Membrane Fluidity; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Dynamics Simulation; Mutation; Protein Conformation, alpha-Helical; Protein Stability; Proteolysis; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction; Stearoyl-CoA Desaturase; Structure-Activity Relationship; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.05.015

Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness. [Display omitted] •Identification of Mga2 as a eukaryotic sensor for lipid saturation•Mga2 uses a rotation-based mechanism of lipid saturation sensing•Mga2 integrates membrane signals to control fatty acid desaturation Poikilothermic organisms adjust their lipid composition to the ambient temperature to maintain membrane fluidity. Covino et al. show that Mga2 uses its transmembrane helix to sense the lipid packing in the ER, thereby controlling the OLE pathway responsible for regulating fatty acid desaturation in Saccharomyces cerevisiae.