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

doi:10.1038/ncomms14893

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 journal › Article › peer-review

67 Scopus citations

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.

Original language	English (US)
Article number	14893
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14893
State	Published - Mar 30 2017
Externally published	Yes

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

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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 {\AA} 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.",

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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).",

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AU - Jaipuria, Garima

AU - Leonov, Andrei

AU - Giller, Karin

AU - Vasa, Suresh Kumar

AU - Jaremko, Áukasz

AU - Jaremko, Mariusz

AU - Linser, Rasmus

AU - Becker, Stefan

AU - Zweckstetter, Markus

N1 - 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).

PY - 2017/3/30

Y1 - 2017/3/30

N2 - 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.

AB - 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.

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Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure

Abstract

Bibliographical note

ASJC Scopus subject areas

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