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Structural and mechanistic insights into MICU 1 regulation of mitochondrial calcium uptake
Author(s) -
Wang Lele,
Yang Xue,
Li Siwei,
Wang Zheng,
Liu Yu,
Feng Jianrong,
Zhu Yushan,
Shen Yuequan
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201386523
Subject(s) - biology , calcium , mitochondrion , computational biology , microbiology and biotechnology , biophysics , organic chemistry , chemistry
Mitochondrial calcium uptake is a critical event in various cellular activities. Two recently identified proteins, the mitochondrial Ca 2+ uniporter ( MCU ), which is the pore‐forming subunit of a Ca 2+ channel, and mitochondrial calcium uptake 1 ( MICU 1), which is the regulator of MCU , are essential in this event. However, the molecular mechanism by which MICU 1 regulates MCU remains elusive. In this study, we report the crystal structures of Ca 2+ ‐free and Ca 2+ ‐bound human MICU 1. Our studies reveal that Ca 2+ ‐free MICU 1 forms a hexamer that binds and inhibits MCU . Upon Ca 2+ binding, MICU 1 undergoes large conformational changes, resulting in the formation of multiple oligomers to activate MCU . Furthermore, we demonstrate that the affinity of MICU 1 for Ca 2+ is approximately 15–20 μM. Collectively, our results provide valuable details to decipher the molecular mechanism of MICU 1 regulation of mitochondrial calcium uptake.