MICU1 motifs define mitochondrial calcium uniporter binding and activity.
MICU1 motifs define mitochondrial calcium uniporter binding and activity.
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DOI：
10.1016/j.celrep.2013.11.026
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发表时间：
2013-12-26
期刊：
影响因子：
8.8
通讯作者：
Madesh M
中科院分区：
文献类型：
--
作者：
Hoffman NE;Chandramoorthy HC;Shamugapriya S;Zhang X;Rajan S;Mallilankaraman K;Gandhirajan RK;Vagnozzi RJ;Ferrer LM;Sreekrishnanilayam K;Natarajaseenivasan K;Vallem S;Force T;Choi ET;Cheung JY;Madesh M
静息线粒体基质Ca2+通过micu1建立的MCU活性阈值抑制来维持。目前尚不清楚MICU1如何与MCU相互作用以建立线粒体Ca2+摄取和MCU活性的Ca2+阈值。在这里，我们发现MICU1定位于线粒体内膜的线粒体基质侧，MICU1/MCU的结合是由MICU1 n端多基结构域和两个相互作用的MCU线圈结构域决定的。进一步的研究表明，MICU1形成同质低聚物，这种低聚化与多基区无关。然而，多碱基区赋予MICU1寡聚物与MCU结合并控制线粒体Ca2+电流（IMCU）。此外，MICU1 EF-hands调节MCU通道活动，但不决定MCU绑定。MICU1的缺失促进MCU激活，导致氧化负担和细胞迁移停止。这些研究建立了MICU1控制mcu介导的线粒体Ca2+积累的分子机制，该机制的失调可能会加剧血管功能障碍。
Resting mitochondrial matrix Ca2+ is maintained through a MICU1-established threshold inhibition of MCU activity. It is not known how MICU1 interacts with MCU to establish this Ca2+ threshold for mitochondrial Ca2+ uptake and MCU activity. Here, we show that MICU1 localizes to the mitochondrial matrix side of the inner mitochondrial membrane and MICU1/MCU binding is determined by a MICU1 N-terminal polybasic domain and two interacting coiled-coil domains of MCU. Further investigation reveals MICU1 forms homo-oligomers, and this oligomerization is independent of the polybasic region. However the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca2+ current (IMCU). Moreover, MICU1 EF-hands regulate MCU channel activity but do not determine MCU binding. Loss of MICU1 promotes MCU activation leading to oxidative burden and a halt to cell migration. These studies establish a molecular mechanism for MICU1 control of MCU-mediated mitochondrial Ca2+ accumulation, and dysregulation of this mechanism likely enhances vascular dysfunction.
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影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
4
作者：
Gyorgy Hajnoczky;Gyrogy Csordas;Yi, Muqing
通讯作者：
Yi, Muqing
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
64.8
作者：
Baughman, Joshua M.;Perocchi, Fabiana;Girgis, Hany S.;Plovanich, Molly;Belcher-Timme, Casey A.;Sancak, Yasemin;Bao, X. Robert;Strittmatter, Laura;Goldberger, Olga;Bogorad, Roman L.;Koteliansky, Victor;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.