The yeast mitochondrial pyruvate carrier is a hetero‐dimer in its functional state. (12th April 2019)

• Record Type: Journal Article
• Authors: Tavoulari, Sotiria; Thangaratnarajah, Chancievan; Mavridou, Vasiliki; Harbour, Michael E; Martinou, Jean‐Claude; Kunji, Edmund RS
• Is Part Of: EMBO journal. Volume 38:Number 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-12
• Subjects: mitochondria -- oligomeric state -- protein complex -- pyruvate -- transport proteins; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018100785
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The mitochondrial pyruvate carrier (MPC) is critical for cellular homeostasis, as it is required in central metabolism for transporting pyruvate from the cytosol into the mitochondrial matrix. MPC has been implicated in many diseases and is being investigated as a drug target. A few years ago, small membrane proteins, called MPC1 and MPC2 in mammals and Mpc1, Mpc2 and Mpc3 in yeast, were proposed to form large protein complexes responsible for this function. However, the MPC complexes have never been isolated and their composition, oligomeric state and functional properties have not been defined. Here, we identify the functional unit of MPC from Saccharomyces cerevisiae . In contrast to earlier hypotheses, we demonstrate that MPC is a hetero‐dimer, not a multimeric complex. When not engaged in hetero‐dimers, the yeast Mpc proteins can also form homo‐dimers that are, however, inactive. We show that the earlier described substrate transport properties and inhibitor profiles are embodied by the hetero‐dimer. This work provides a foundation for elucidating the structure of the functional complex and the mechanism of substrate transport and inhibition. Synopsis: Yeast mitochondrial pyruvate carrier (MPC) has been proposed to be a multimeric complex containing different combinations of three MPC protomers. Here, heterodimers of Mpc1/Mpc3 and Mpc1/Mpc2 are found to constitute the functional units of MPC complex in respiratory and fermentative conditions, respectively. Mitochondrial pyruvate carrier complexes from Saccharomyces cerevisiae are purified and functionally reconstituted into liposomes. Reconstituted Mpc1/Mpc3 and Mpc1/Mpc2 complexes transport pyruvate in a pH‐gradient‐dependent manner and are inhibited by known MPC inhibitors. Individual Mpc proteins can form homodimers, which are however not functional. Abstract : Mpc1/Mpc3 and Mpc1/Mpc2 heterodimers constitute the functional unit of yeast mitochondrial pyruvate carrier complex in respiratory and fermentative conditions, respectively.