| Structural highlights
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]
Publication Abstract from PubMed
The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti-/pro-apoptosis and necrosis by several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N-terminal domain (NTD) at a resolution of 1.50 A in a novel fold and the S92A MCU mutant at 2.75 A resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake-1 and mitochondrial calcium uptake-2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca2+ uptake in a stable MCU knockdown HeLa cell line and exerted dominant-negative effects in the wild-type MCU-expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation.
Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter.,Lee Y, Min CK, Kim TG, Song HK, Lim Y, Kim D, Shin K, Kang M, Kang JY, Youn HS, Lee JG, An JY, Park KR, Lim JJ, Kim JH, Kim JH, Park ZY, Kim YS, Wang J, Kim DH, Eom SH EMBO Rep. 2015 Sep 3. pii: e201540436. PMID:26341627[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
- ↑ Lee Y, Min CK, Kim TG, Song HK, Lim Y, Kim D, Shin K, Kang M, Kang JY, Youn HS, Lee JG, An JY, Park KR, Lim JJ, Kim JH, Kim JH, Park ZY, Kim YS, Wang J, Kim DH, Eom SH. Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep. 2015 Sep 3. pii: e201540436. PMID:26341627 doi:https://dx.doi.org/10.15252/embr.201540436
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