title: Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure.
abstract: Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer-dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer. Consistent with an allosteric mechanism, a mutation within the oligomerization interface perturbs transmembrane regions located up to 35 Å away from the interface, reaching TSPO's cholesterol-binding motif. The lower structural stability of the intervening transmembrane regions provides a mechanistic basis for signal transmission. Our study thus reveals an allosteric signal pathway that connects membrane protein tertiary and quaternary structure with cholesterol binding.
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany.
authors.forename: Garima
authors.initials: G
authors.lastname: Jaipuria
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Leonov
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Vasa
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Jaremko
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Jaremko
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Linser
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany.|Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen, Germany.|Department of Neurology, University Medical Center Göttingen, University of Göttingen, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018079:Receptors, GABA / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C463819:Bzrp protein, mouse; D008051:Lipid Bilayers; D018079:Receptors, GABA; D002784:Cholesterol