1. Structural Basis of Membrane Protein Chaperoning through the Mitochondrial Intermembrane Space.
- Author
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Weinhäupl K, Lindau C, Hessel A, Wang Y, Schütze C, Jores T, Melchionda L, Schönfisch B, Kalbacher H, Bersch B, Rapaport D, Brennich M, Lindorff-Larsen K, Wiedemann N, and Schanda P
- Subjects
- Amino Acid Sequence, Binding Sites, Intracellular Membranes metabolism, Mitochondrial Membrane Transport Proteins chemistry, Mitochondrial Membrane Transport Proteins genetics, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Binding, Protein Domains, Protein Precursors chemistry, Protein Precursors metabolism, Protein Structure, Secondary, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins chemistry, Saccharomyces cerevisiae Proteins genetics, Sequence Alignment, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins metabolism, Molecular Chaperones metabolism, Saccharomyces cerevisiae Proteins metabolism
- 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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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