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The structure of the MICU 1‐ MICU 2 complex unveils the regulation of the mitochondrial calcium uniporter
Author(s) -
Wu Wenping,
Shen Qingya,
Zhang Ruiling,
Qiu Zhiyu,
Wang Youjun,
Zheng Jimin,
Jia Zongchao
Publication year - 2020
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 - 10.15252/embj.2019104285
Subject(s) - beijing , china , chinese academy of sciences , library science , chemistry , political science , computer science , law
Abstract The MICU 1‐ MICU 2 heterodimer regulates the mitochondrial calcium uniporter ( MCU ) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU 1‐ MICU 2 heterodimer, in which Ca 2+ ‐free and Ca 2+ ‐bound EF ‐hands are observed in both proteins, revealing both electrostatic and hydrophobic interfaces. Furthermore, we show that MICU 1 interacts with EMRE , another regulator of MCU , through a Ca 2+ ‐dependent alkaline groove. Ca 2+ binding strengthens the MICU 1‐ EMRE interaction, which in turn facilitates Ca 2+ uptake. Conversely, the MICU 1‐ MCU interaction is favored in the absence of Ca 2+ , thus inhibiting the channel activity. This Ca 2+ ‐dependent switch illuminates how calcium signals are transmitted from regulatory subunits to the calcium channel and the transition between gatekeeping and activation channel functions. Furthermore, competition with an EMRE peptide alters the uniporter threshold in resting conditions and elevates Ca 2+ accumulation in stimulated mitochondria, confirming the gatekeeper role of the MICU 1‐ MICU 2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake.