Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter

Youngjin Lee, Choon Kee Min, Tae Gyun Kim, Hong Ki Song, Yunki Lim, Dongwook Kim, Kahee Shin, Moonkyung Kang, Jung Youn Kang, Hyung Seop Youn, Jung Gyu Lee, Jun Yop An, Kyoung Ryoung Park, Jia Jia Lim, Ji Hun Kim, Ji Hye Kim, Zee Yong Park, Yeon Soo Kim, Jimin Wang, Do Han KimSoo Hyun Eom

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75 Citations (Scopus)


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 Ca2+ 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.

Original languageEnglish
Pages (from-to)1318-1333
Number of pages16
JournalEMBO Reports
Issue number10
Publication statusPublished - Oct 2015
Externally publishedYes


  • crystal structure
  • MCU
  • MCU domain-like fold
  • mitochondrial calcium uptake
  • uniplex

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