Abstract
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.
Highlights
Mitochondria, well known as the “powerhouses of the cell”, are major places to synthesize ATP through oxidative phosphorylation (OXPHOS) in eukaryotes
Substrates transported by mitochondrial carriers (MCs) are extremely diversified, these transporters all have three homologous domains (Figure 1a), and each domain contains many conserved sequence motifs such as [YF][DE]xx[RK], GxxxG and πxxxπ motifs [3] near the cytoplasmic side of the carriers and more conserved mitochondrial carrier family (MCF) motif near the matrix side: Px[DE]xx[KR]xRxxQ-(matrix loop)-[YF]xG-(matrix helix)-[DE]Gxxxx[YWF][KR]G [2,3,4]
The special tripartite symmetry in sequence and highly conserved MCF motif in each homologous domain distinguish this family from other transporter families
Summary
Mitochondria, well known as the “powerhouses of the cell”, are major places to synthesize ATP through oxidative phosphorylation (OXPHOS) in eukaryotes. As the semi-autonomous organelles, mitochondria need to replicate their own DNA, and transcribe and translate genes they carry. To fulfill these functions, solutes including ions, nucleotides, amino acids, fatty acids and many other important metabolites need to be continuously exchanged between cytoplasm and mitochondrial matrix. Members of the mitochondrial carrier family (MCF) facilitate transport of these substrates across the highly impermeable inner mitochondrial membrane (IMM) [1,2,3]. 53 members have been identified in human MCF This family represents the biggest solute carrier (SLC) subfamily and is known as SLC25
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