Mitochondrial carrier proteins

Mitochondrial carrier proteins transport metabolites between the mitochondrial matrix and cytoplasm.

Figure. In patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome, one of the residues in the carrier that bind to ornithine is mutated from a glutamate to a lysine residue, preventing the substrate from binding and being transported into the mitochondrion.

We study the mitochondrial carrier proteins in collaboration with Dr. Edmund Kunji. An atomic-resolution structure of the bovine ADP/ATP carrier was solved in complex with the inhibitor carboxyatractyloside by Dr. Peyroula and colleagues. However this did not show the substrate binding site or mechanism of substrate translocation across the inner mitochondrial membrane. With Edmund Kunji, we identified residues likely responsible for substrate binding  [1-2]. By understanding the binding site, we were able to change the specificty of a carrier [10]. 

Further research proposed a transport mechanism for the mitochondrial carriers [3] and how the carriers may use protons to drive the uptake of substrates against a concentration gradient [4]. We collaborated with colleagues to validate how the mitochondrial carriers function [5-7], as well as the identification of novel carriers in pathogens [8] and their role in disease [9].

Using the knowledge we have acquired about the transport mechanism and function of mitochondrial carriers, we are now studying how they can be used as drug targets.

Resources

References

  1. Robinson, A. J. and Kunji E. R. S. (2006). Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc. Natl. Acad. Sci. U. S. A., 103, 2617-2622.
  2. Kunji, E. R. S. and Robinson, A. J. (2006). The conserved substrate binding site of the mitochondrial carriers. Biochim. Biophys. Acta., 1757, 1237-1248.
  3. Robinson, A. J., Overy, C. and Kunji, E. R. S. (2008).
 The mechanism of transport by mitochondrial carriers based on analysis of symmetry. 
Proc. Natl. Acad. Sci. U. S. A., 105, 17766-17771.
  4. Kunji, E. R. S. & Robinson, A. J. (2010).
Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers.
 Opinion in Structural Biology, 20, 440-447.
  5. Cappello, A. R., Curcio, R., Miniero, D. V., Stipani, I., Robinson, A. J., Kunji, E. R. S. and Palmieri, F. (2006).
 Functional and structural role of amino acid residues in the even-numbered transmembrane α-helices of the bovine mitochondrial oxoglutarate carrier. 
J. Mol. Biol., 363, 51-62.
  6. Cappello, A. R., Miniero, D. V., Curcio, R., Ludovico, A., Daddabbo, L., Stipani, I., Robinson, A. J., Kunji, E. R. S. and Palmieri, F. (2007).
Functional and structural role of amino acid residues in the odd-numbered transmembrane α-helices of the bovine mitochondrial oxoglutarate carrier.
 J. Mol. Biol., 369, 400-412.
  7. Miniero, D. V., Cappello, A. R., Curcio, R., Ludovic, A., Daddabbo, L., Stipani, I., Robinson, A. J., Kunji, E. R. S. and Palmieri, F. (2011).
Functional and structural role of amino acid residues in the matrix alpha-helices, termini and cytosolic loopes of the bovine mitochondrial oxoglutarate carrier.
 Biochim. Biophys. Acta., 1807, 302-310.
  8. Monné, M., Robinson, A. J., Boes, C., Harbour, M. E., Fearnley, I. M. and Kunji, E. R. S. (2007).
The mimivirus genome encodes a mitochondrial carrier that transports dATP and dTTP. 
J. Virol., 81, 3181-3186.
  9. Robinson, A. J., Kunji, E. R. S. & Gross, A. (2012).
 Mitochondrial carrier homolog 2 (MTCH2): The recruitment and evolution of a mitochondrial carrier protein to a critical player in apoptosis.
 Exp. Cell Res, 318, 1316-1323.
  10. Monné, M., Miniero, D. V., Daddabbo, L., Robinson, A., Kunji, E. R. S. & Palmieri, F. (2012). The substrate specificity of the two mitochondrial ornithine carriers can be swapped by a single mutation in the substrate binding site. J. Biol. Chem. 287, 7925-7934.