Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure

Garima Jaipuria, Andrei Leonov, Karin Giller, Suresh Kumar Vasa, Áukasz Jaremko, Mariusz Jaremko, Rasmus Linser, Stefan Becker, Markus Zweckstetter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Article number14893
JournalNature Communications
StatePublished - Mar 30 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Nasrollah Rezaei-Ghaleh for discussions about TSPO oligomerization and Brigitta Angerstein for help with packing of solid-state rotors. This work was supported by the DFG Collaborative Research Center 803 (project A11 to M.Z.), the European Research Council (grant agreement number 282008) and the Erwin Neher Nobel Fellowship (to M.J.). R.L. acknowledges a Liebig junior group fellowship (VCI) and Emmy-Noether Funding (DFG).

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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