Targeting, import, and dimerization of a mammalian mitochondrial ATP binding cassette (ABC) transporter, ABCB10 (ABC-me) (original) (raw)

Mitochondrial ABC proteins in health and disease

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2009

ABC transporters represent one of the largest families of membrane proteins that are found in all three phyla of life. Mitochondria comprise up to four ABC systems, ABCB7/ATM1, ABCB10/MDL1, ABCB8 and ABCB6. These half-transporters, which assemble into homodimeric complexes, are involved in a number of key cellular processes, e.g. biogenesis of cytosolic iron-sulfur clusters, heme biosynthesis, iron homeostasis, multidrug resistance, and protection against oxidative stress. Here, we summarize recent advances and emerging themes in our understanding of how these ABC systems in the inner and outer mitochondrial membrane fulfill their functions in important (patho) physiological processes, including neurodegenerative and hematological disorders.

Structure and function of mitochondrial carriers – Role of the transmembrane helix P and G residues in the gating and transport mechanism

FEBS Letters, 2010

Keywords: Membrane protein Mitochondrial carrier Mitochondrial carrier disease Mitochondrial carrier proline and glycine Transporter structure Transport mechanism a b s t r a c t To date, 22 mitochondrial carrier subfamilies have been functionally identified based on substrate specificity. Structural, functional and bioinformatics studies have pointed to the existence in the mitochondrial carrier superfamily of a substrate-binding site in the internal carrier cavity, of two salt-bridge networks or gates that close the cavity alternatively on the matrix or the cytosolic side of the membrane, and of conserved prolines and glycines in the transmembrane a-helices. The significance of these properties in the structural changes occurring during the catalytic substrate translocation cycle are discussed within the context of a transport mechanism model. Most experimentally produced and disease-causing missense mutations concern carrier regions corresponding to the substrate-binding site, the two gates and the conserved prolines and glycines.

Biogenesis of yeast dicarboxylate carrier: the carrier signature facilitates translocation across the mitochondrial outer membrane

Journal of Cell Science, 2007

Aquila, H., Misra, D., Eulitz, M. and Klingenberg, M. (1982). Complete amino acid sequence of the ADP/ATP carrier from beef heart mitochondria. . The carboxyl-terminal third of the dicarboxylate carrier is crucial for productive association with the inner membrane twin-pore translocase. J. Biol. Chem. 280, 6215-6221. Brix, J., Ziegler, G. A., Dietmeier, K., Schneider-Mergener, J., Schulz, G. E. and Pfanner, N. (2000). The mitochondrial import receptor Tom70: identification of a 25 kDa core domain with a specific binding site for preproteins. . The mitochondrial oxoglutarate carrier: sulfhydryl reagents bind to cysteine-184, and this interaction is enhanced by substrate binding. Biochemistry 35, 8974-8980. . (2007). Functional and structural role of amino acid residues in the odd-numbered transmembrane alpha-helices of the bovine mitochondrial oxoglutarate carrier. (2000). Two intermembrane space TIM complexes interact with different domains of Tim23p during its import into mitochondria. J. Cell Biol. 150, 1271-1282. de Marcos-Lousa, C., Sideris, D. P. and Tokatlidis, K. (2006). Translocation of mitochondrial inner-membrane proteins: conformation matters. Trends Biochem. Sci. 31, 259-267. Endres, M., Neupert, W. and Brunner, M. (1999). Transport of the ADP/ATP carrier of mitochondria from the TOM complex to the TIM22.54 complex. EMBO J. 18, 3214-3221. Fiermonte, G., Palmieri, L., Dolce, V., Lasorsa, F. M., Palmieri, F., Runswick, M. J. and Walker, J. E. (1998). The sequence, bacterial expression, and functional reconstitution of the rat mitochondrial dicarboxylate transporter cloned via distant homologs in yeast and Caenorhabditis elegans. . (1995). High level expression and characterization of the mitochondrial citrate transport protein from the yeast Saccharomyces cerevisiae.

Shifting the Paradigm: The Putative Mitochondrial Protein ABCB6 Resides in the Lysosomes of Cells and in the Plasma Membrane of Erythrocytes

PLOS One, 2012

ABCB6, a member of the adenosine triphosphate-binding cassette (ABC) transporter family, has been proposed to be responsible for the mitochondrial uptake of porphyrins. Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation. Consistent with its presence in exosomes, endogenous ABCB6 is localized to the endo/lysosomal compartment, and is absent from the mitochondria of cells. Knock-down studies demonstrate that ABCB6 function is not required for de novo heme biosynthesis in differentiating K562 cells, excluding this ABC transporter as a key regulator of porphyrin synthesis. We confirm the mitochondrial localization of ABCB7, ABCB8 and ABCB10, suggesting that only three ABC transporters should be classified as mitochondrial proteins. Taken together, our results challenge the current paradigm linking the expression and function of ABCB6 to mitochondria.

Selective and ATP-dependent Translocation of Peptides by the Homodimeric ATP Binding Cassette Transporter TAP-like (ABCB9)

Journal of Biological Chemistry, 2005

The transporter associated with antigen processing (TAP)-like (TAPL, ABCB9) belongs to the ATP-binding cassette transporter family, which translocates a vast variety of solutes across membranes. The function of this half-size transporter has not yet been determined. Here, we show that TAPL forms a homodimeric complex, which translocates peptides across the membrane. Peptide transport strictly requires ATP hydrolysis. The transport follows Michaelis-Menten kinetics with low affinity and high capacity. Different nucleotides bind and energize the transport with a slight predilection for purine bases. The peptide specificity is very broad, ranging from 6-mer up to at least 59-mer peptides with a preference for 23-mers. Peptides are recognized via their backbone, including the free N and C termini as well as side chain interactions. Although related to TAP, TAPL is unique as far as its interaction partners, transport properties, and substrate specificities are concerned, thus excluding that TAPL is part of the peptideloading complex in the classic route of antigen processing via major histocompatibility complex class I molecules.

Mitochondrial ADP/ATP Carrier: Preventing Conformational Changes by Point Mutations Inactivates Nucleotide Transport Activity

Biochemistry, 2012

The mitochondrial ADP/ATP carrier (Ancp) is a paradigm of the mitochondrial carrier family (MCF); its members allow metabolic fluxes between mitochondria and the cytosol. The members of the MCF share numerous structural and functional characteristics. Ancp is very specifically inhibited by two classes of compounds, which stabilize the carrier in two different conformations involved in nucleotide transport. Resolution of the atomic structure of the bovine Ancp, in complex with one of its specific inhibitors, is that of the carrier open toward the intermembrane space. To gain insights into the interconversion from one conformation to the other, we introduced point mutations in the yeast carrier at positions Cys73 in the first matrix loop and Tyr97 and Gly298 in transmembrane helices 2 and 6. We demonstrate in this paper that they impair stabilization of the carrier in one conformation or the other, resulting in an almost complete inactivation of nucleotide transport in both cases. The results are discussed on the basis of the atomic structure of the conformation open to the cytosol. These mutant proteins could afford convenient tools for undertaking structural studies of both conformations of the yeast carrier.