Mitochondrial carriers belong to a large family of membrane proteins
(MCF for Mitochondrial Carrier Family) located in the inner
mitochondrial membrane and implicated in the transport of many important
metabolites. They share several common features. In particular, their
amino-acid sequence consists of a repeat of about 100 aminoacids
resulting from a probable gene “triplication”. Each repeat comprises a
conserved amino-acid motif, characteristic of the family (MCF motif).
The ADP/ATP carrier (AAC) is the most studied MCF carrier and we solved
its structure in the presence of strong inhibitor, CATR
carboxyatractyloside (Pebay-Peyroula et al., Nature 2003). The
importance of the MCF motifs in the structure indicates that all MCF
carriers should have a similar fold. However, all the carriers are
highly specific and the transported substrates differ drastically in
size and chemical nature. Although, the current structure shed light in
to the ADP binding site exposed to the inter membrane space (Nury et
al., Ann. Rev. Biochem. 2006), it does not fully explain the
specificity. In addition, the conformational changes awaited for the
transport still remain to be elucidated. In order to understand the
specificity and transport mechanism, we are studying two MCF carriers:
AAC and UCP (uncoupling protein) which transports a proton. In the
recent years, we set up different tools to produce these proteins
(Blesneac et al., BBA Biomembranes 2012) and to functionally
characterize their function (Blesneac et al., Eur. Biophys., J. 2012).
In collaboration with C. Chipot and his team, we examined the first
steps of the transport in light with molecular dynamics simulations
(Dehez et al., JACS 2008). We also explored the properties of several
mutations responsible for severe diseases (Ravaud et al., ACS Chem.
Biol. 2012). All these approaches will help in coupling structural and
functional data and thus allow to decipher the molecular mechanism of
transport.