| Structural highlights
6wdn is a 10 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | MICU2, EFHA1 (HUMAN), MICU1, CALC, CBARA1 (HUMAN), SMDT1, C22orf32, EMRE (HUMAN), MCU, C10orf42, CCDC109A (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[MCU_HUMAN] Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Activity is regulated by MICU1 and MICU2 that stimulate and inhibit MCU activity, respectively. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [MICU2_HUMAN] Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low (PubMed:24503055, PubMed:24560927, PubMed:26903221). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium (PubMed:24560927). MICU2 acts as a gatekeeper of MCU that senses calcium level via its EF-hand domains: prevents channel opening at resting calcium, avoiding energy dissipation and cell-death triggering (PubMed:24560927).[10] [11] [12] [13] [EMRE_HUMAN] Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988).[14] [15] [16] [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.[17] [18] [19] [20]
Publication Abstract from PubMed
Mitochondria take up Ca(2+) through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca(2+) signalling and cell death(1,2). In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca(2+) transport(3-8). To prevent detrimental Ca(2+) overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca(2+) concentrations to switch MCU on and off(9,10). Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca(2+)-activated states. These structures define the architecture of this multicomponent Ca(2+)-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca(2+) uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca(2+) overload.
Structure and mechanism of the mitochondrial Ca(2+) uniporter holocomplex.,Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M, Xu Y, Liao M, Tsai MF, Feng L Nature. 2020 Jun;582(7810):129-133. doi: 10.1038/s41586-020-2309-6. Epub 2020 May, 20. PMID:32494073[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011 Jun 19;476(7360):341-5. doi: 10.1038/nature10234. PMID:21685886 doi:https://dx.doi.org/10.1038/nature10234
- ↑ De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011 Jun 19;476(7360):336-40. doi: 10.1038/nature10230. PMID:21685888 doi:https://dx.doi.org/10.1038/nature10230
- ↑ Drago I, De Stefani D, Rizzuto R, Pozzan T. Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):12986-91. doi:, 10.1073/pnas.1210718109. Epub 2012 Jul 20. PMID:22822213 doi:https://dx.doi.org/10.1073/pnas.1210718109
- ↑ Tarasov AI, Semplici F, Ravier MA, Bellomo EA, Pullen TJ, Gilon P, Sekler I, Rizzuto R, Rutter GA. The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. PLoS One. 2012;7(7):e39722. doi: 10.1371/journal.pone.0039722. Epub 2012 Jul 19. PMID:22829870 doi:https://dx.doi.org/10.1371/journal.pone.0039722
- ↑ 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:https://dx.doi.org/10.1074/jbc.M112.392084
- ↑ 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:https://dx.doi.org/10.1016/j.cell.2012.10.011
- ↑ Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol. 2012 Dec;14(12):1336-43. doi: 10.1038/ncb2622. Epub 2012 Nov 25. PMID:23178883 doi:https://dx.doi.org/10.1038/ncb2622
- ↑ Hoffman NE, Chandramoorthy HC, Shamugapriya S, Zhang X, Rajan S, Mallilankaraman K, Gandhirajan RK, Vagnozzi RJ, Ferrer LM, Sreekrishnanilayam K, Natarajaseenivasan K, Vallem S, Force T, Choi ET, Cheung JY, Madesh M. MICU1 motifs define mitochondrial calcium uniporter binding and activity. Cell Rep. 2013 Dec 26;5(6):1576-88. doi: 10.1016/j.celrep.2013.11.026. Epub 2013 , Dec 12. PMID:24332854 doi:https://dx.doi.org/10.1016/j.celrep.2013.11.026
- ↑ Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell. 2014 Mar 6;53(5):726-37. doi: 10.1016/j.molcel.2014.01.013. Epub 2014, Feb 20. PMID:24560927 doi:https://dx.doi.org/10.1016/j.molcel.2014.01.013
- ↑ Kamer KJ, Mootha VK. MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep. 2014 Mar;15(3):299-307. doi: 10.1002/embr.201337946. Epub 2014 Feb 6. PMID:24503055 doi:https://dx.doi.org/10.1002/embr.201337946
- ↑ Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell. 2014 Mar 6;53(5):726-37. doi: 10.1016/j.molcel.2014.01.013. Epub 2014, Feb 20. PMID:24560927 doi:https://dx.doi.org/10.1016/j.molcel.2014.01.013
- ↑ Petrungaro C, Zimmermann KM, Kuttner V, Fischer M, Dengjel J, Bogeski I, Riemer J. The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. Cell Metab. 2015 Oct 6;22(4):721-33. doi: 10.1016/j.cmet.2015.08.019. Epub 2015, Sep 17. PMID:26387864 doi:https://dx.doi.org/10.1016/j.cmet.2015.08.019
- ↑ Matesanz-Isabel J, Arias-del-Val J, Alvarez-Illera P, Fonteriz RI, Montero M, Alvarez J. Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) uptake. Biochim Biophys Acta. 2016 Jun;1858(6):1110-7. doi: 10.1016/j.bbamem.2016.02.022., Epub 2016 Feb 18. PMID:26903221 doi:https://dx.doi.org/10.1016/j.bbamem.2016.02.022
- ↑ Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science. 2013 Dec 13;342(6164):1379-82. doi: 10.1126/science.1242993. Epub 2013, Nov 14. PMID:24231807 doi:https://dx.doi.org/10.1126/science.1242993
- ↑ Vais H, Mallilankaraman K, Mak DD, Hoff H, Payne R, Tanis JE, Foskett JK. EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter. Cell Rep. 2016 Jan 26;14(3):403-410. doi: 10.1016/j.celrep.2015.12.054. Epub 2016, Jan 7. PMID:26774479 doi:https://dx.doi.org/10.1016/j.celrep.2015.12.054
- ↑ Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y, Willliams C, Miller C. Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife. 2016 Apr 21;5. doi: 10.7554/eLife.15545. PMID:27099988 doi:https://dx.doi.org/10.7554/eLife.15545
- ↑ 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:https://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:https://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:https://dx.doi.org/10.1074/jbc.M112.392084
- ↑ Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M, Xu Y, Liao M, Tsai MF, Feng L. Structure and mechanism of the mitochondrial Ca(2+) uniporter holocomplex. Nature. 2020 Jun;582(7810):129-133. doi: 10.1038/s41586-020-2309-6. Epub 2020 May, 20. PMID:32494073 doi:https://dx.doi.org/10.1038/s41586-020-2309-6
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