Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex.
Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex.
复制标题
线粒体钙单一转运体复合体中依赖EmRE的MCU开放机制。
DOI：
10.1016/j.celrep.2020.108486
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发表时间：
2020-12-08
期刊：
影响因子：
8.8
通讯作者：
Tsai MF
中科院分区：
文献类型：
--
作者：
Van Keuren AM;Tsai CW;Balderas E;Rodriguez MX;Chaudhuri D;Tsai MF
线粒体钙单向转运体是一种多亚基钙激活的钙通道，由成孔MCU蛋白、后生动物特异性EMRE亚基和介导钙激活的MICU 1/MICU 2组成。已经确定后生动物MCU需要EMRE结合来传导Ca 2+，但EMRE如何促进MCU开放仍不清楚。在这里，我们证明了EMRE通过其跨膜螺旋控制MCU活性，同时使用N-末端PKP基序来加强与MCU的结合。MCU的打开需要由靠近孔的腔端的MCU残基介导的疏水相互作用。通过单突变增强这些相互作用允许人类MCU在没有EMRE的情况下转运Ca 2+。我们进一步表明，EMRE可以促进MCU开放，通过稳定的开放状态，在一个保守的MCU门控机制，目前也在非后生动物MCU同系物。这些结果提供了见解的uniporter机制的演变，并阐明了生理上至关重要的EMRE依赖的MCU激活过程的机制。线粒体钙单向转运体是一种多亚基离子通道，将细胞质Ca 2+输入线粒体以调节细胞能量产生和死亡。在这项工作中，货车Keuren等报道了单向转运体的关键激活机制，由通道复合物中的辅助EMRE亚基介导。
The mitochondrial calcium uniporter is a multi-subunit Ca2+-activated Ca2+ channel, made up of the pore-forming MCU protein, a metazoan-specific EMRE subunit, and MICU1/MICU2, which mediate Ca2+ activation. It has been established that metazoan MCU requires EMRE binding to conduct Ca2+, but how EMRE promotes MCU opening remains unclear. Here, we demonstrate that EMRE controls MCU activity via its transmembrane helix, while using an N-terminal PKP motif to strengthen binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore’s luminal end. Enhancing these interactions by single mutation allows human MCU to transport Ca2+ without EMRE. We further show that EMRE may facilitate MCU opening by stabilizing the open state in a conserved MCU gating mechanism, present also in non-metazoan MCU homologs. These results provide insights into the evolution of the uniporter machinery and elucidate the mechanism underlying the physiologically crucial EMRE-dependent MCU activation process. The mitochondrial calcium uniporter is a multi-subunit ion channel that imports cytoplasmic Ca2+ into mitochondria to regulate cell energy production and death. In this work, Van Keuren et al. report a key activation mechanism of the uniporter, mediated by an auxiliary EMRE subunit in the channel complex.
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影响因子：
64.5
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DOI：
10.1073/pnas.1702938114
发表时间：
2017-04-25
影响因子：
11.1
作者：
Tsai, Chen-Wei;Wu, Yujiao;Tsai, Ming-Feng
通讯作者：
Tsai, Ming-Feng
DOI：
10.1126/science.1242993
发表时间：
2013-12-13
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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通讯作者：
Mootha VK