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 Kim; Soo Hyun Eom

doi:10.15252/embr.201540436

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

Research output: Contribution to journal › Article › Research › peer-review

71 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	1318-1333
Number of pages	16
Journal	EMBO Reports
Volume	16
Issue number	10
DOIs	https://doi.org/10.15252/embr.201540436
Publication status	Published - Oct 2015
Externally published	Yes

Keywords

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

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Lee, Y., Min, C. K., Kim, T. G., Song, H. K., Lim, Y., Kim, D., Shin, K., Kang, M., Kang, J. Y., Youn, H. S., Lee, J. G., An, J. Y., Park, K. R., Lim, J. J., Kim, J. H., Kim, J. H., Park, Z. Y., Kim, Y. S., Wang, J., ... Eom, S. H. (2015). Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Reports, 16(10), 1318-1333. https://doi.org/10.15252/embr.201540436

@article{0f75e5c829f74dba9b01c759b10d5572,

title = "Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter",

abstract = "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 {\AA} in a novel fold and the S92A MCU mutant at 2.75 {\AA} 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.",

keywords = "crystal structure, MCU, MCU domain-like fold, mitochondrial calcium uptake, uniplex",

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

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = oct,

doi = "10.15252/embr.201540436",

language = "English",

volume = "16",

pages = "1318--1333",

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Lee, Y, Min, CK, Kim, TG, Song, HK, Lim, Y, Kim, D, Shin, K, Kang, M, Kang, JY, Youn, HS, Lee, JG, An, JY, Park, KR, Lim, JJ, Kim, JH, Kim, JH, Park, ZY, Kim, YS, Wang, J, Kim, DH & Eom, SH 2015, 'Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter', EMBO Reports, vol. 16, no. 10, pp. 1318-1333. https://doi.org/10.15252/embr.201540436

TY - JOUR

T1 - Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter

AU - Lee, Youngjin

AU - Min, Choon Kee

AU - Kim, Tae Gyun

AU - Song, Hong Ki

AU - Lim, Yunki

AU - Kim, Dongwook

AU - Shin, Kahee

AU - Kang, Moonkyung

AU - Kang, Jung Youn

AU - Youn, Hyung Seop

AU - Lee, Jung Gyu

AU - An, Jun Yop

AU - Park, Kyoung Ryoung

AU - Lim, Jia Jia

AU - Kim, Ji Hun

AU - Kim, Ji Hye

AU - Park, Zee Yong

AU - Kim, Yeon Soo

AU - Wang, Jimin

AU - Kim, Do Han

AU - Eom, Soo Hyun

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

KW - crystal structure

KW - MCU

KW - MCU domain-like fold

KW - mitochondrial calcium uptake

KW - uniplex

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U2 - 10.15252/embr.201540436

DO - 10.15252/embr.201540436

M3 - Article

C2 - 26341627

AN - SCOPUS:84942776229

VL - 16

SP - 1318

EP - 1333

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 10

ER -

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

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Keywords

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