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Cell. 2019 Jan 24;176(3):435-447.e15. doi: 10.1016/j.cell.2018.11.025. Epub 2019 Jan 2.

The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier.

Author information

1
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: jjr@mrc-mbu.cam.ac.uk.
2
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
3
VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
4
Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
5
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: ek@mrc-mbu.cam.ac.uk.

Abstract

Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family. VIDEO ABSTRACT.

KEYWORDS:

adenine nucleotide translocase; adenine nucleotide translocator; alternating access mechanism; bioenergetics; bongkrekate; cardiolipin; induced fit; mitochondria; transport mechanism

PMID:
30611538
PMCID:
PMC6349463
DOI:
10.1016/j.cell.2018.11.025
[Indexed for MEDLINE]
Free PMC Article

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