A molecular insight to the mitochondrial ADP/ATP carrier

ITQB Seminar

Title: A molecular insight to the mitochondrial ADP/ATP carrier

Speaker: Eva Pebay-Peyroula

Affiliation: Institut de Biologie Structurale, Grenoble

Host: Margarida Archer, Macromolecular Cristallography Unit

Abstract:

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.