The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex
The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex
复制标题
MCU保守的天冬氨酸环介导MICU1在线粒体单转运钙复合体中的结合和调控
DOI：
10.7554/elife.41112
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发表时间：
2019-01-15
期刊：
影响因子：
7.7
通讯作者：
Tsai, Ming-Feng
中科院分区：
文献类型：
--
作者：
Phillips, Charles B.;Tsai, Chen-Wei;Tsai, Ming-Feng
线粒体钙单向转运蛋白是一种钙离子通道，调节细胞内钙离子信号传导、氧化磷酸化和细胞凋亡。它含有成孔MCU蛋白，其具有被认为形成Ca 2+选择性过滤器的DIME序列，以及调节EMRE、MICU 1和MICU 2亚基。为了正确地执行生理功能，单向转运蛋白必须在静息条件下保持关闭，只有在受到细胞内Ca 2+信号刺激时才会打开。这种Ca 2+依赖性激活，已知是由MICU亚基介导的，还没有得到很好的理解。在这里，我们证明，DIME-天冬氨酸介导的钙离子调节的静电相互作用与MICU 1，形成一个MICU 1接触界面附近的丝氨酸残基在细胞质入口处的MCU孔。MICU 1的诱变筛选鉴定了可能接触DIME-Asp的两个高度保守的Arg残基。干扰MCU-MICU 1相互作用导致未受调节的组成型Ca 2+流入线粒体。这些结果表明，MICU 1通过阻断/解除阻断MCU赋予单向转运体的Ca 2+依赖性门控。
The mitochondrial calcium uniporter is a Ca2+ channel that regulates intracellular Ca2+ signaling, oxidative phosphorylation, and apoptosis. It contains the pore-forming MCU protein, which possesses a DIME sequence thought to form a Ca2+ selectivity filter, and also regulatory EMRE, MICU1, and MICU2 subunits. To properly carry out physiological functions, the uniporter must stay closed in resting conditions, becoming open only when stimulated by intracellular Ca2+ signals. This Ca2+-dependent activation, known to be mediated by MICU subunits, is not well understood. Here, we demonstrate that the DIME-aspartate mediates a Ca2+-modulated electrostatic interaction with MICU1, forming an MICU1 contact interface with a nearby Ser residue at the cytoplasmic entrance of the MCU pore. A mutagenesis screen of MICU1 identifies two highly-conserved Arg residues that might contact the DIME-Asp. Perturbing MCU-MICU1 interactions elicits unregulated, constitutive Ca2+ flux into mitochondria. These results indicate that MICU1 confers Ca2+-dependent gating of the uniporter by blocking/unblocking MCU.