Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
EMBO J. 2019 May 15;38(10). doi: 10.15252/embj.2018100785. Epub 2019 Apr 12.
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 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.
线粒体丙酮酸载体 (MPC) 对细胞内稳态至关重要，因为它在中央代谢中需要将细胞质中的丙酮酸转运到线粒体基质中。MPC 与许多疾病有关，并且正在被作为药物靶点进行研究。几年前，有人提出，一些称为哺乳动物中的 MPC1 和 MPC2 以及酵母中的 Mpc1、Mpc2 和 Mpc3 的小膜蛋白，形成负责这一功能的大型蛋白复合物。然而，MPC 复合物从未被分离出来，其组成、寡聚状态和功能特性尚未确定。在这里，我们从酵母中鉴定出 MPC 的功能单位。与早期的假设相反，我们证明 MPC 是一种异二聚体，而不是多聚体复合物。当不形成异二聚体时，酵母 Mpc 蛋白也可以形成无活性的同二聚体。我们表明，先前描述的底物转运特性和抑制剂谱由异二聚体体现。这项工作为阐明功能复合物的结构以及底物转运和抑制的机制奠定了基础。
