Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States.
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2020 Aug 7;9:e60513. doi: 10.7554/eLife.60513.
Mitochondrial Ca uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca-dependent manner. Here, we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca, revealing distinct Ca dependent assembly of the uniplex. Our structural observations suggest that Ca changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.
线粒体 Ca 摄取是由一种称为线粒体钙单向转运蛋白的线粒体内膜蛋白介导的。在人类中，单向转运蛋白作为一个完整复合物发挥作用，该复合物由 MCU、EMRE、MICU1 和 MICU2 组成，其中 MCU 和 EMRE 形成一个亚复合物并作为导电通道发挥作用，而 MICU1 和 MICU2 是 EF 手蛋白，以 Ca 依赖的方式调节通道活性。在这里，我们展示了存在和不存在 Ca 的情况下人线粒体钙单向转运蛋白完整复合物（uniplex）的 EM 结构，揭示了 uniplex 的独特的 Ca 依赖性组装。我们的结构观察表明，Ca 改变了 MICU1 和 MICU2 之间的二聚相互作用，这反过来又决定了 MICU1-MICU2 亚复合物与 MCU-EMRE 通道的相互作用方式，从而改变了 uniplex 组装体在阻塞和非阻塞状态之间的分布。
