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Structural highlights
6o5b is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | CA |
| Gene: | MCU, C10orf42, CCDC109A (HUMAN), SMDT1, C22orf32, EMRE (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] [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).[10] [11] [12]
Publication Abstract from PubMed
Mitochondrial calcium uptake is crucial to the regulation of eukaryotic Ca(2+) homeostasis and is mediated by the mitochondrial calcium uniporter (MCU). While MCU alone can transport Ca(2+) in primitive eukaryotes, metazoans require an essential single membrane-spanning auxiliary component called EMRE to form functional channels; however, the molecular mechanism of EMRE regulation remains elusive. Here, we present the cryo-EM structure of the human MCU-EMRE complex, which defines the interactions between MCU and EMRE as well as pinpoints the juxtamembrane loop of MCU and extended linker of EMRE as the crucial elements in the EMRE-dependent gating mechanism among metazoan MCUs. The structure also features the dimerization of two MCU-EMRE complexes along an interface at the N-terminal domain (NTD) of human MCU that is a hotspot for post-translational modifications. Thus, the human MCU-EMRE complex, which constitutes the minimal channel components among metazoans, provides a framework for future mechanistic studies on MCU.
Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter.,Wang Y, Nguyen NX, She J, Zeng W, Yang Y, Bai XC, Jiang Y Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub, 2019 May 9. PMID:31080062[13]
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
- ↑ 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
- ↑ Wang Y, Nguyen NX, She J, Zeng W, Yang Y, Bai XC, Jiang Y. Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter. Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub, 2019 May 9. PMID:31080062 doi:https://dx.doi.org/10.1016/j.cell.2019.03.050
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