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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Biological Transport
  • Bongkrekic Acid / metabolism
  • Cytoplasm / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Mitochondrial ADP, ATP Translocases / metabolism*
  • Mitochondrial ADP, ATP Translocases / physiology
  • Mitochondrial ADP, ATP Translocases / ultrastructure*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membrane Transport Proteins / physiology
  • Mitochondrial Membrane Transport Proteins / ultrastructure
  • Models, Molecular
  • Protein Conformation
  • Protein Structure, Secondary
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Mitochondrial Membrane Transport Proteins
  • Saccharomyces cerevisiae Proteins
  • Bongkrekic Acid
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Mitochondrial ADP, ATP Translocases