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Cell. 2018 Nov 15;175(5):1365-1379.e25. doi: 10.1016/j.cell.2018.10.039.

Structural Basis of Membrane Protein Chaperoning through the Mitochondrial Intermembrane Space.

Author information

1
Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS, 71 Avenue des Martyrs, 38000 Grenoble, France.
2
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
3
Structural Biology and NMR Laboratory, the Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
4
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
5
Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
6
European Molecular Biology Laboratory, 38042 Grenoble, France.
7
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. Electronic address: nils.wiedemann@biochemie.uni-freiburg.de.
8
Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS, 71 Avenue des Martyrs, 38000 Grenoble, France. Electronic address: paul.schanda@ibs.fr.

Abstract

The exchange of metabolites between the mitochondrial matrix and the cytosol depends on β-barrel channels in the outer membrane and α-helical carrier proteins in the inner membrane. The essential translocase of the inner membrane (TIM) chaperones escort these proteins through the intermembrane space, but the structural and mechanistic details remain elusive. We have used an integrated structural biology approach to reveal the functional principle of TIM chaperones. Multiple clamp-like binding sites hold the mitochondrial membrane proteins in a translocation-competent elongated form, thus mimicking characteristics of co-translational membrane insertion. The bound preprotein undergoes conformational dynamics within the chaperone binding clefts, pointing to a multitude of dynamic local binding events. Mutations in these binding sites cause cell death or growth defects associated with impairment of carrier and β-barrel protein biogenesis. Our work reveals how a single mitochondrial "transfer-chaperone" system is able to guide α-helical and β-barrel membrane proteins in a "nascent chain-like" conformation through a ribosome-free compartment.

KEYWORDS:

NMR spectroscopy; TIM complex; binding by avidity; membrane protein; mitochondria; molecular dynamics simulation; protein import; protein translocation; small-angle X-ray scattering; transfer-chaperone

PMID:
30445040
PMCID:
PMC6242696
DOI:
10.1016/j.cell.2018.10.039
[Indexed for MEDLINE]
Free PMC Article

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