The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex,iScience

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The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex
iScience ( IF 4.6 ) Pub Date : 2024-04-10 , DOI: 10.1016/j.isci.2024.109699
Megan Noble ₁ , Danielle M Colussi ₁ , Murray Junop ₂ , Peter B Stathopulos ₁

Affiliation

The mitochondrial calcium (Ca) uniporter (MCU) complex is regulated via integration of the MCU dominant negative beta subunit (MCUb), a low conductance paralog of the main MCU pore forming protein. The MCU amino (N)-terminal domain (NTD) also modulates channel function through cation binding to the MCU regulating acidic patch (MRAP). MCU and MCUb have high sequence similarities, yet the structural and functional roles of MCUb-NTD remain unknown. Here, we report that MCUb-NTD exhibits α-helix/β-sheet structure with a high thermal stability, dependent on protein concentration. Remarkably, MCU- and MCUb-NTDs heteromerically interact with ∼nM affinity, increasing secondary structure and stability and structurally perturbing MRAP. Further, we demonstrate MCU and MCUb co-localization is suppressed upon NTD deletion concomitant with increased mitochondrial Ca uptake. Collectively, our data show that MCU:MCUb NTD tight interactions are promoted by enhanced regular structure and stability, augmenting MCU:MCUb co-localization, lowering mitochondrial Ca uptake and implicating an MRAP-sensing mechanism.

中文翻译：

MCU 和 MCUb 氨基末端结构域紧密相互作用：线粒体钙单向转运蛋白复合物低电导组装的机制

线粒体钙 (Ca) 单向转运蛋白 (MCU) 复合物通过 MCU 显性负 β 亚基 (MCUb) 的整合进行调节，MCUb 是主要 MCU 孔形成蛋白的低电导旁系同源物。 MCU 氨基 (N) 末端结构域 (NTD) 还通过与 MCU 调节酸性补丁 (MRAP) 的阳离子结合来调节通道功能。 MCU 和 MCUb 具有高度的序列相似性，但 MCUb-NTD 的结构和功能作用仍不清楚。在这里，我们报告 MCUb-NTD 表现出 α-螺旋/β-折叠结构，具有高热稳定性，取决于蛋白质浓度。值得注意的是，MCU-和 MCUb-NTD 与 ~nM 亲和力异聚相互作用，增加了二级结构和稳定性，并在结构上扰乱了 MRAP。此外，我们证明当 NTD 缺失同时线粒体 Ca 摄取增加时，MCU 和 MCUb 共定位受到抑制。总的来说，我们的数据表明，MCU:MCUb NTD 紧密相互作用是通过增强规则结构和稳定性、增强 MCU:MCUb 共定位、降低线粒体 Ca 摄取并暗示 MRAP 传感机制来促进的。

更新日期：2024-04-10

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