Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-02, Vol.27 (3), p.1071
Main Authors: Yao, Shihao, Ma, Boyuan, Yi, Qiuzi, Guan, Min-Xin, Cang, Xiaohui
Format: Article
Language:English
Subjects:
Adenosine diphosphate
ADP/ATP carrier
Amino Acid Motifs
Asymmetry
ATP
Atractyloside - analogs & derivatives
Atractyloside - chemistry
Atractyloside - pharmacology
Binding Sites
Bridges
Crystal structure
Cytosol
Imports
Mitochondria
Mitochondria - metabolism
Mitochondrial ADP, ATP Translocases - chemistry
Mitochondrial ADP, ATP Translocases - genetics
Mitochondrial ADP, ATP Translocases - metabolism
mitochondrial carrier family
Models, Molecular
Molecular dynamics
Molecular Dynamics Simulation
Mutation
Protein Binding
Protein Conformation
Residues
Simulation
Symmetry
transporter
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Summary:The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27031071