| Structural highlights
Function
MICU1_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 PubMed
The 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 Also
References
- ↑ Aichberger KJ, Mittermann I, Reininger R, Seiberler S, Swoboda I, Spitzauer S, Kopp T, Stingl G, Sperr WR, Valent P, Repa A, Bohle B, Kraft D, Valenta R. Hom s 4, an IgE-reactive autoantigen belonging to a new subfamily of calcium-binding proteins, can induce Th cell type 1-mediated autoreactivity. J Immunol. 2005 Jul 15;175(2):1286-94. PMID:16002733
- ↑ Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 2010 Sep 16;467(7313):291-6. doi: 10.1038/nature09358. Epub 2010 Aug 8. PMID:20693986 doi:http://dx.doi.org/10.1038/nature09358
- ↑ Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell. 2012 Oct 26;151(3):630-44. doi: 10.1016/j.cell.2012.10.011. PMID:23101630 doi:http://dx.doi.org/10.1016/j.cell.2012.10.011
- ↑ Alam MR, Groschner LN, Parichatikanond W, Kuo L, Bondarenko AI, Rost R, Waldeck-Weiermair M, Malli R, Graier WF. Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic beta-cells. J Biol Chem. 2012 Oct 5;287(41):34445-54. doi: 10.1074/jbc.M112.392084. Epub 2012, Aug 17. PMID:22904319 doi:http://dx.doi.org/10.1074/jbc.M112.392084
- ↑ Wu W, Shen Q, Zhang R, Qiu Z, Wang Y, Zheng J, Jia Z. The structure of the MICU1-MICU2 complex unveils the regulation of the mitochondrial calcium uniporter. EMBO J. 2020 Oct 1;39(19):e104285. PMID:32790952 doi:10.15252/embj.2019104285
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