Lee Youngjin, Min Choon Kee, Kim Tae Gyun, Song Hong Ki, Lim Yunki, Kim Dongwook, Shin Kahee, Kang Moonkyung, Kang Jung Youn, Youn Hyung-Seop, Lee Jung-Gyu, An Jun Yop, Park Kyoung Ryoung, Lim Jia Jia, Kim Ji Hun, Kim Ji Hye, Park Zee Yong, Kim Yeon-Soo, Wang Jimin, Kim Do Han, Eom Soo Hyun
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
EMBO Rep. 2015 Oct;16(10):1318-33. doi: 10.15252/embr.201540436. Epub 2015 Sep 3.
The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti-/pro-apoptosis and necrosis by several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N-terminal domain (NTD) at a resolution of 1.50 Å in a novel fold and the S92A MCU mutant at 2.75 Å resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake-1 and mitochondrial calcium uptake-2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca(2+) uptake in a stable MCU knockdown HeLa cell line and exerted dominant-negative effects in the wild-type MCU-expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation.
线粒体钙单向转运体（MCU）负责线粒体对钙的摄取及稳态平衡。它也是多个癌基因和肿瘤抑制因子调控细胞抗凋亡/促凋亡及坏死过程的作用靶点。在此，我们报道了MCU N端结构域（NTD）分辨率为1.50 Å的晶体结构，其具有新颖的折叠方式，以及分辨率为2.75 Å的S92A MCU突变体结构；残基S92是预测的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）磷酸化位点。线粒体钙单向转运体复合物（单聚体）的组装以及与MCU调节因子如线粒体钙摄取蛋白1和线粒体钙摄取蛋白2（MICU1和MICU2）的相互作用不受MCU NTD缺失的影响。然而，S92A突变体或NTD缺失突变体的表达未能在稳定敲低MCU的HeLa细胞系中恢复线粒体Ca(2+)摄取，并且在表达野生型MCU的细胞系中发挥显性负效应。这些结果表明，MCU的NTD对于MCU功能的调节至关重要，尽管它不影响单聚体的形成。
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