Transport mechanism of mitochondrial carriers

The inner mitochondrial membrane contains a superfamily of proteins, called mitochondrial carriers (MCs), which transport several metabolites into and out of the mitochondrial matrix. As observed in the ADP/ATP carrier structure, crystallized in complex with its powerful inhibitor carboxyatractyloside, the main structural fold of the MCs consists of a barrel of six transmembrane α-helices whose charged surfaces form the wall of a water-filled cavity. Multiple sequence alignment and 3D comparative models of mitochondrial carriers of known function have recently allowed the identification of i) a similarly located binding site located in the carrier cavity, ii) two ion pair networks or gates that are on the matrix or the cytosolic side of the carrier molecules, and iii) two Pro-Gly levels above and below the substrate binding site. As a result of the substrate–protein interactions, ‘hinged helix movements’ consisting of a tilt of the entire helical segments and a kink/swivel of the helical termini at the level of their Pro and Gly have been proposed to be fundamental for the alternative opening and closure of the gates on the matrix or the cytosolic side and thus for the translocation mechanism. The key role of residues of the binding site, gates and Pro-Gly levels in substrate translocation is supported by the localization of most missense mutations found in patients affected by diseases associated to mitochondrial carriers. References Klingenberg M (2007 ) Transport viewed as a catalytic process. Biochimie. 89:1042-8. Palmieri F (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta 1777: 564-57 Palmieri F, Pierri CL (2010) Structure and function of mitochondrial carriers - Role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett. 584:1931-9 Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trézéguet V, Lauquin GJ, Brandolin G. (2003) Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature. 426:39-44 Robinson AJ, Kunji ER. (2006) Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc Natl Acad Sci U S A. 103:2617-22 Robinson AJ, Overy C, Kunji ER. (2008) The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A. 105:17766-71 Wibom R, Lasorsa F, Töhönen V, Barbaro M, Sterky F, Kucinski T, Naess K, Jonsson M, Pierri CL, Palmieri F, Wedell A (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 361: 489-495