The mechanism of transport by mitochondrial carriers based on analysis of symmetry.
The structures of mitochondrial transporters and uncoupling proteins are 3-fold pseudosymmetrical, but their substrates and coupling ions are not. Thus, deviations from symmetry are to be expected in the substrate and ion-binding sites in the central aqueous cavity. By analyzing the 3-fold pseudosymmetrical repeats from which their sequences are made, conserved asymmetric residues were found to cluster in a region of the central cavity identified previously as the common substrate-binding site. Conserved symmetrical residues required for the transport mechanism were found at the water-membrane interfaces, and they include the three PX[DE]XX[RK] motifs, which form a salt bridge network on the matrix side of the cavity when the substrate-binding site is open to the mitochondrial intermembrane space. Symmetrical residues in three [FY][DE]XX[RK] motifs are on the cytoplasmic side of the cavity and could form a salt bridge network when the substrate-binding site is accessible from the mitochondrial matrix. It is proposed that the opening and closing of the carrier may be coupled to the disruption and formation of the 2 salt bridge networks via a 3-fold rotary twist induced by substrate binding. The interaction energies of the networks allow members of the transporter family to be classified as strict exchangers or uniporters.
Robinson
Alan J
AJ
Medical Research Council, Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 0XY, United Kingdom. ajr@mrc-dunn.cam.ac.uk
Overy
Catherine
C
Kunji
Edmund R S
ER
D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry
D029701:Saccharomyces cerevisiae Proteins; D000226:Mitochondrial ADP, ATP Translocases