Journal
EMBO REPORTS
Volume 16, Issue 10, Pages 1318-1333Publisher
WILEY
DOI: 10.15252/embr.201540436
Keywords
crystal structure; MCU; MCU domain-like fold; mitochondrial calcium uptake; uniplex
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Funding
- National Research Foundation (NRF) [2013M3A9A7046297, 2013R1A2A2A01068440, 2007-0056157, 2013R1A1A2062629]
- BK21 Plus Program
- GIST Systems Biology Infrastructure Establishment Grant, South Korea
- National Research Foundation of Korea [2013M3A9A7046297, 2007-0056157, 2013R1A2A2A01068440, 2013R1A1A2062629] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 angstrom in a novel fold and the S92A MCU mutant at 2.75 angstrom 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.
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