A Eukaryotic Sensor for Membrane Lipid Saturation.
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.
Department of Theoretical Biophysics, Max-Planck-Institute of Biophysics, 60438 Frankfurt, Germany.
Roberto
R
Covino
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany.
Stephanie
S
Ballweg
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany.
Claudius
C
Stordeur
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany.
Jonas B
JB
Michaelis
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany.
Kristina
K
Puth
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany.
Florian
F
Wernig
Department of Theoretical Biophysics, Max-Planck-Institute of Biophysics, 60438 Frankfurt, Germany.
Amir
A
Bahrami
Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06510, USA.
Andreas M
AM
Ernst
Department of Theoretical Biophysics, Max-Planck-Institute of Biophysics, 60438 Frankfurt, Germany.
Gerhard
G
Hummer
Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany. Electronic address: ernst@em.uni-frankfurt.de.
Robert
R
Ernst
D004578:Electron Spin Resonance Spectroscopy; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D007425:Intracellular Membranes / Q000378:metabolism*; D008560:Membrane Fluidity; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000072756:Protein Conformation, alpha-Helical; D055550:Protein Stability; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D005227:Fatty Acids; C542266:MGA2 protein, S cerevisiae; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase