MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Physiology, Semmelweis University, Budapest, 1094 Hungary.
Mol Cell. 2018 Nov 15;72(4):778-785.e3. doi: 10.1016/j.molcel.2018.09.008. Epub 2018 Oct 25.
Proper control of the mitochondrial Ca uniporter's pore (MCU) is required to allow Ca-dependent activation of oxidative metabolism and to avoid mitochondrial Ca overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter.
适当控制线粒体钙单向转运蛋白（MCU）的孔道对于允许钙依赖性激活氧化代谢以及避免线粒体钙过载和细胞死亡是必需的。MCU 的门控和协同激活由钙感应的 MCU1 蛋白介导，该蛋白已被提议形成二聚体复合物，锚定在 MCU 的 EMRE 支架上。我们出人意料地发现，MCU1 抑制了钌红/Ru360 对 MCU 的抑制，后者结合 MCU 的 DIME 基序，即选择性过滤器。这使我们在 MCU1 的序列中识别出一个假定的 DIME 相互作用域（DID），该域对于 MCU 的门控和协同激活以及细胞存活都是必需的。因此，我们提出 MCU1 必须与 MCU 中的 DIME 结构域形成的 D 环相互作用，以控制单向转运蛋白。
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