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Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure

Author

Listed:
  • Garima Jaipuria

    (Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))

  • Andrei Leonov

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Karin Giller

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Suresh Kumar Vasa

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Łukasz Jaremko

    (Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))

  • Mariusz Jaremko

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Rasmus Linser

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Stefan Becker

    (Max-Planck-Institut für Biophysikalische Chemie)

  • Markus Zweckstetter

    (Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
    Max-Planck-Institut für Biophysikalische Chemie
    University Medical Center Göttingen, University of Göttingen)

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.

Suggested Citation

  • Garima Jaipuria & Andrei Leonov & Karin Giller & Suresh Kumar Vasa & Łukasz Jaremko & Mariusz Jaremko & Rasmus Linser & Stefan Becker & Markus Zweckstetter, 2017. "Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14893
    DOI: 10.1038/ncomms14893
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