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Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ruprecht, Jonathan J  ORCID logo  https://orcid.org/0000-0002-1838-7245
Palmer, Shane M 

Abstract

Mitochondrial ADP/ATP carriers import ADP into the mitochondrial matrix and export ATP to the cytosol to fuel cellular processes. Structures of the inhibited cytoplasmic- and matrix-open states have confirmed an alternating access transport mechanism, but the molecular details of substrate binding remain unresolved. Here, we evaluate the role of the solvent-exposed residues of the translocation pathway in the process of substrate binding. We identify the main binding site, comprising three positively charged and a set of aliphatic and aromatic residues, which bind ADP and ATP in both states. Additionally, there are two pairs of asparagine/arginine residues on opposite sides of this site that are involved in substrate binding in a state-dependent manner. Thus, the substrates are directed through a series of binding poses, inducing the conformational changes of the carrier that lead to their translocation. The properties of this site explain the electrogenic and reversible nature of adenine nucleotide transport.

Description

Keywords

Adenosine Diphosphate, Adenosine Triphosphate, Binding Sites, Cytoplasm, Mitochondria, Mitochondrial ADP, ATP Translocases

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (MC_UU_00015/1)
MRC (MC_UU_00028/2)
Medical Research Council (MC_UU_00015/1)
Medical Research Council (MC_UU_00015/7)