6lb7
From Proteopedia
Crystal structure of the Ca2+-free and Ca2+-bound MICU1-MICU2 complex
Structural highlights
FunctionMICU1_HUMAN Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low. Acts as a gatekeeper that senses calcium level via its EF-hand domains and sets a threshold for mitochondrial calcium uptake by MCU, thereby preventing mitochondrial calcium overload. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG.[1] [2] [3] [4] Publication Abstract from PubMedThe MICU1-MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU1-MICU2 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 MICU1 interacts with EMRE, another regulator of MCU, through a Ca(2+) -dependent alkaline groove. Ca(2+) binding strengthens the MICU1-EMRE interaction, which in turn facilitates Ca(2+) uptake. Conversely, the MICU1-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 MICU1-MICU2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake. The structure of the MICU1-MICU2 complex unveils the regulation of the mitochondrial calcium uniporter.,Wu W, Shen Q, Zhang R, Qiu Z, Wang Y, Zheng J, Jia Z EMBO J. 2020 Oct 1;39(19):e104285. doi: 10.15252/embj.2019104285. Epub 2020 Aug , 13. PMID:32790952[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Jia Z | Shen Q | Wu W | Zheng J
