| 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
Calcium (Ca2+) flux into the matrix is tightly controlled by the mitochondrial Ca2+ uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a beta-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca2+ or Mg2+ destabilizes and shifts the self-association equilibrium of the domain toward monomer. Mutational disruption of the acidic face weakens oligomerization of the isolated matrix domain and full-length human protein similar to cation binding and markedly decreases MCU activity. Moreover, mitochondrial Mg2+ loading or blockade of mitochondrial Ca2+ extrusion suppresses MCU Ca2+-uptake rates. Collectively, our data reveal that the beta-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to Mg2+ and Ca2+ binding.
Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations.,Lee SK, Shanmughapriya S, Mok MC, Dong Z, Tomar D, Carvalho E, Rajan S, Junop MS, Madesh M, Stathopulos PB Cell Chem Biol. 2016 Aug 24. pii: S2451-9456(16)30242-2. doi:, 10.1016/j.chembiol.2016.07.012. PMID:27569754[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 SK, Shanmughapriya S, Mok MC, Dong Z, Tomar D, Carvalho E, Rajan S, Junop MS, Madesh M, Stathopulos PB. Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations. Cell Chem Biol. 2016 Aug 24. pii: S2451-9456(16)30242-2. doi:, 10.1016/j.chembiol.2016.07.012. PMID:27569754 doi:https://dx.doi.org/10.1016/j.chembiol.2016.07.012
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