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From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation

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Membrane Dynamics and Calcium Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 981))

Abstract

All eukaryotic cells have adapted the use of the calcium ion (Ca2+) as a universal signaling element through the evolution of a toolkit of Ca2+ sensor, buffer and effector proteins. Among these toolkit components, integral and peripheral proteins decorate biomembranes and coordinate the movement of Ca2+ between compartments, sense these concentration changes and elicit physiological signals. These changes in compartmentalized Ca2+ levels are not mutually exclusive as signals propagate between compartments. For example, agonist induced surface receptor stimulation can lead to transient increases in cytosolic Ca2+ sourced from endoplasmic reticulum (ER) stores; the decrease in ER luminal Ca2+ can subsequently signal the opening surface channels which permit the movement of Ca2+ from the extracellular space to the cytosol. Remarkably, the minuscule compartments of mitochondria can function as significant cytosolic Ca2+ sinks by taking up Ca2+ in a coordinated manner. In non-excitable cells, inositol 1,4,5 trisphosphate receptors (IP3Rs) on the ER respond to surface receptor stimulation; stromal interaction molecules (STIMs) sense the ER luminal Ca2+ depletion and activate surface Orai1 channels; surface Orai1 channels selectively permit the movement of Ca2+ from the extracellular space to the cytosol; uptake of Ca2+ into the matrix through the mitochondrial Ca2+ uniporter (MCU) further shapes the cytosolic Ca2+ levels. Recent structural elucidations of these key Ca2+ toolkit components have improved our understanding of how they function to orchestrate precise cytosolic Ca2+ levels for specific physiological responses. This chapter reviews the atomic-resolution structures of IP3R, STIM1, Orai1 and MCU elucidated by X-ray crystallography, electron microscopy and NMR and discusses the mechanisms underlying their biological functions in their respective compartments within the cell.

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References

  1. Berridge MJ (2009) Cell signalling biology. Portland, London

    Google Scholar 

  2. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529

    Article  CAS  PubMed  Google Scholar 

  3. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21

    Article  CAS  PubMed  Google Scholar 

  4. Bootman MD, Collins TJ, Peppiatt CM, Prothero LS, MacKenzie L, De Smet P, Travers M, Tovey SC, Seo JT, Berridge MJ, Ciccolini F, Lipp P (2001) Calcium signalling – an overview. Semin Cell Dev Biol 12:3–10

    Article  CAS  PubMed  Google Scholar 

  5. Bootman MD, Lipp P (2001) Calcium signalling and regulation of cell function. In: Encyclopedia of Life Sciences. p 1–7

    Google Scholar 

  6. Bootman MD, Lipp P, Berridge MJ (2001) The organisation and functions of local Ca2+ signals. J Cell Sci 114:2213–2222

    CAS  PubMed  Google Scholar 

  7. Balshaw D, Gao L, Meissner G (1999) Luminal loop of the ryanodine receptor: a pore-forming segment? Proc Natl Acad Sci USA 96:3345–3347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702

    Article  CAS  PubMed  Google Scholar 

  9. Tu H, Nosyreva E, Miyakawa T, Wang Z, Mizushima A, Iino M, Bezprozvanny I (2003) Functional and biochemical analysis of the type 1 inositol (1,4,5)-trisphosphate receptor calcium sensor. Biophys J 85:290–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alonso MT, Villalobos C, Chamero P, Alvarez J, Garcia-Sancho J (2006) Calcium microdomains in mitochondria and nucleus. Cell Calcium 40:513–525

    Article  CAS  PubMed  Google Scholar 

  11. Kadamur G, Ross EM (2013) Mammalian phospholipase C. Annu Rev Physiol 75:127–154

    Article  CAS  PubMed  Google Scholar 

  12. Fedorenko OA, Popugaeva E, Enomoto M, Stathopulos PB, Ikura M, Bezprozvanny I (2014) Intracellular calcium channels: inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39–48

    Article  CAS  PubMed  Google Scholar 

  13. Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378

    Article  CAS  PubMed  Google Scholar 

  14. MacLennan DH (2000) Ca2+ signalling and muscle disease. Eur J Biochem 267:5291–5297

    Article  CAS  PubMed  Google Scholar 

  15. Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12

    Article  CAS  PubMed  Google Scholar 

  16. Stathopulos PB, Ikura M (2016) Store operated calcium entry: from concept to structural mechanisms. Cell Calcium 63:3–7

    Article  CAS  PubMed  Google Scholar 

  17. Andersen TB, Lopez CQ, Manczak T, Martinez K, Simonsen HT (2015) Thapsigargin – from Thapsia L. to mipsagargin. Molecules 20:6113–6127

    Article  CAS  PubMed  Google Scholar 

  18. Hogan PG (2017) Calcium-NFAT transcriptional signalling in T cell activation and T cell exhaustion. Cell Calcium 63:66–69

    Article  CAS  PubMed  Google Scholar 

  19. Deak AT, Blass S, Khan MJ, Groschner LN, Waldeck-Weiermair M, Hallstrom S, Graier WF, Malli R (2014) IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. J Cell Sci 127:2944–2955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fonteriz R, Matesanz-Isabel J, Arias-Del-Val J, Alvarez-Illera P, Montero M, Alvarez J (2016) Modulation of calcium entry by mitochondria. Adv Exp Med Biol 898:405–421

    Article  CAS  PubMed  Google Scholar 

  21. Kopach O, Kruglikov I, Pivneva T, Voitenko N, Verkhratsky A, Fedirko N (2011) Mitochondria adjust Ca(2+) signaling regime to a pattern of stimulation in salivary acinar cells. Biochim Biophys Acta 1813:1740–1748

    Article  CAS  PubMed  Google Scholar 

  22. Ma T, Gong K, Yan Y, Song B, Zhang X, Gong Y (2012) Mitochondrial modulation of store-operated Ca(2+) entry in model cells of Alzheimer’s disease. Biochem Biophys Res Commun 426:196–202

    Article  CAS  PubMed  Google Scholar 

  23. Tang S, Wang X, Shen Q, Yang X, Yu C, Cai C, Cai G, Meng X, Zou F (2015) Mitochondrial Ca2+ uniporter is critical for store-operated Ca2+ entry-dependent breast cancer cell migration. Biochem Biophys Res Commun 458:186–193

    Article  CAS  PubMed  Google Scholar 

  24. Marchi S, Pinton P (2014) The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications. J Physiol 592:829–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Patron M, Raffaello A, Granatiero V, Tosatto A, Merli G, De Stefani D, Wright L, Pallafacchina G, Terrin A, Mammucari C, Rizzuto R (2013) The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles. J Biol Chem 288:10750–10758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Carafoli E (2003) Historical review: mitochondria and calcium: ups and downs of an unusual relationship. Trends Biochem Sci 28:175–181

    Article  CAS  PubMed  Google Scholar 

  27. Raffaello A, De Stefani D, Rizzuto R (2012) The mitochondrial Ca(2+) uniporter. Cell Calcium 52:16–21

    Article  CAS  PubMed  Google Scholar 

  28. Orrenius S, Gogvadze V, Zhivotovsky B (2015) Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun 460:72–81

    Article  CAS  PubMed  Google Scholar 

  29. Drago I, Pizzo P, Pozzan T (2011) After half a century mitochondrial calcium in- and efflux machineries reveal themselves. EMBO J 30:4119–4125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brini M, Carafoli E (2000) Calcium signalling: a historical account, recent developments and future perspectives. Cell Mol Life Sci 57:354–370

    Article  CAS  PubMed  Google Scholar 

  31. De Stefani D, Rizzuto R, Pozzan T (2016) Enjoy the trip: calcium in mitochondria back and forth. Annu Rev Biochem 85:161–192

    Article  CAS  PubMed  Google Scholar 

  32. Nita LI, Hershfinkel M, Sekler I (2015) Life after the birth of the mitochondrial Na+/Ca2+ exchanger, NCLX. Sci China Life Sci 58:59–65

    Article  CAS  PubMed  Google Scholar 

  33. Carafoli E, Balcavage WX, Lehninger AL, Mattoon JR (1970) Ca2+ metabolism in yeast cells and mitochondria. Biochim Biophys Acta 205:18–26

    Article  CAS  PubMed  Google Scholar 

  34. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (2006) Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc Natl Acad Sci USA 103:9357–9362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185

    Article  CAS  PubMed  Google Scholar 

  38. Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr (2006) Large store-operated calcium-selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281:24979–24990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233

    Article  CAS  PubMed  Google Scholar 

  40. Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R (2006) CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16:2073–2079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Feske S (2012) Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci 1238:74–90

    Article  CAS  Google Scholar 

  44. 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 (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabo I, Rizzuto R (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32:2362–2376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, Speciner L, Taneja N, Oshea J, Koteliansky V, Mootha VK (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8:e55785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379–1382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hoffman NE, Chandramoorthy HC, Shanmughapriya S, Zhang XQ, Vallem S, Doonan PJ, Malliankaraman K, Guo S, Rajan S, Elrod JW, Koch WJ, Cheung JY, Madesh M (2014) SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. Mol Biol Cell 25:936–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA, Dale P, Li C, Ames JB, Ikura M, Taylor CW (2012) Structural and functional conservation of key domains in InsP3 and ryanodine receptors. Nature 483:108–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lin CC, Baek K, Lu Z (2011) Apo and InsP(3)-bound crystal structures of the ligand-binding domain of an InsP(3) receptor. Nat Struct Mol Biol 18:1172–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chan J, Yamazaki H, Ishiyama N, Seo MD, Mal TK, Michikawa T, Mikoshiba K, Ikura M (2010) Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating. J Biol Chem 285:36092–36099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bosanac I, Yamazaki H, Matsu-Ura T, Michikawa T, Mikoshiba K, Ikura M (2005) Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor. Mol Cell 17:193–203

    Article  CAS  PubMed  Google Scholar 

  56. Bosanac I, Alattia JR, Mal TK, Chan J, Talarico S, Tong FK, Tong KI, Yoshikawa F, Furuichi T, Iwai M, Michikawa T, Mikoshiba K, Ikura M (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420:696–700

    Article  CAS  PubMed  Google Scholar 

  57. Ding Z, Rossi AM, Riley AM, Rahman T, Potter BV, Taylor CW (2010) Binding of inositol 1,4,5-trisphosphate (IP3) and adenophostin A to the N-terminal region of the IP3 receptor: thermodynamic analysis using fluorescence polarization with a novel IP3 receptor ligand. Mol Pharmacol 77:995–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rossi AM, Taylor CW (2013) High-throughput fluorescence polarization assay of ligand binding to IP3 receptors. Cold Spring Harb Protoc 2013:938–946

    Article  PubMed  Google Scholar 

  59. Sipma H, De Smet P, Sienaert I, Vanlingen S, Missiaen L, Parys JB, De Smedt H (1999) Modulation of inositol 1,4,5-trisphosphate binding to the recombinant ligand-binding site of the type-1 inositol 1,4, 5-trisphosphate receptor by Ca2+ and calmodulin. J Biol Chem 274:12157–12162

    Article  CAS  PubMed  Google Scholar 

  60. Vanlingen S, Sipma H, De Smet P, Callewaert G, Missiaen L, De Smedt H, Parys JB (2001) Modulation of inositol 1,4,5-trisphosphate binding to the various inositol 1,4,5-trisphosphate receptor isoforms by thimerosal and cyclic ADP-ribose. Biochem Pharmacol 61:803–809

    Article  CAS  PubMed  Google Scholar 

  61. Yoshikawa F, Iwasaki H, Michikawa T, Furuichi T, Mikoshiba K (1999) Cooperative formation of the ligand-binding site of the inositol 1,4, 5-trisphosphate receptor by two separable domains. J Biol Chem 274:328–334

    Article  CAS  PubMed  Google Scholar 

  62. Yoshikawa F, Uchiyama T, Iwasaki H, Tomomori-Satoh C, Tanaka T, Furuichi T, Mikoshiba K (1999) High efficient expression of the functional ligand binding site of the inositol 1,4,5-triphosphate receptor in Escherichia coli. Biochem Biophys Res Commun 257:792–797

    Article  CAS  PubMed  Google Scholar 

  63. Li C, Enomoto M, Rossi AM, Seo MD, Rahman T, Stathopulos PB, Taylor CW, Ikura M, Ames JB (2013) CaBP1, a neuronal Ca2+ sensor protein, inhibits inositol trisphosphate receptors by clamping intersubunit interactions. Proc Natl Acad Sci USA 110:8507–8512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yoshikawa F, Morita M, Monkawa T, Michikawa T, Furuichi T, Mikoshiba K (1996) Mutational analysis of the ligand binding site of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 271:18277–18284

    Article  CAS  PubMed  Google Scholar 

  65. Yamazaki H, Chan J, Ikura M, Michikawa T, Mikoshiba K (2010) Tyr-167/Trp-168 in type 1/3 inositol 1,4,5-trisphosphate receptor mediates functional coupling between ligand binding and channel opening. J Biol Chem 285:36081–36091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rossi AM, Riley AM, Tovey SC, Rahman T, Dellis O, Taylor EJ, Veresov VG, Potter BV, Taylor CW (2009) Synthetic partial agonists reveal key steps in IP3 receptor activation. Nature Chem Biol 5:631–639

    Article  CAS  Google Scholar 

  67. Murray SC, Flanagan J, Popova OB, Chiu W, Ludtke SJ, Serysheva II (2013) Validation of cryo-EM structure of IP(3)R1 channel. Structure 21:900–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ludtke SJ, Tran TP, Ngo QT, Moiseenkova-Bell VY, Chiu W, Serysheva II (2011) Flexible architecture of IP3R1 by Cryo-EM. Structure 19:1192–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Haynes LP, Tepikin AV, Burgoyne RD (2004) Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling. J Biol Chem 279:547–555

    Article  CAS  PubMed  Google Scholar 

  70. Li C, Chan J, Haeseleer F, Mikoshiba K, Palczewski K, Ikura M, Ames JB (2009) Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1. J Biol Chem 284:2472–2481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Park S, Li C, Ames JB (2010) 1H, 15N, and 13C chemical shift assignments of calcium-binding protein 1 with Ca2+ bound at EF1, EF3 and EF4. Biomol NMR Assign 4:159–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang J, McBride S, Mak DO, Vardi N, Palczewski K, Haeseleer F, Foskett JK (2002) Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels. Proc Natl Acad Sci USA 99:7711–7716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Clarke OB, Hendrickson WA (2016) Structures of the colossal RyR1 calcium release channel. Curr Opin Struct Biol 39:144–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hernandez-Ochoa EO, Pratt SJ, Lovering RM, Schneider MF (2015) Critical role of intracellular RyR1 calcium release channels in skeletal muscle function and disease. Front Physiol 6:420

    PubMed  Google Scholar 

  75. Landstrom AP, Dobrev D, Wehrens XHT (2017) Calcium signaling and cardiac arrhythmias. Circ Res 120:1969–1993

    Article  CAS  PubMed  Google Scholar 

  76. Leong P, MacLennan DH (1998) Complex interactions between skeletal muscle ryanodine receptor and dihydropyridine receptor proteins. Biochem Cell Biol 76:681–694

    Article  CAS  PubMed  Google Scholar 

  77. Van Petegem F (2015) Ryanodine receptors: allosteric ion channel giants. J Mol Biol 427:31–53

    Article  CAS  PubMed  Google Scholar 

  78. Yuchi Z, Van Petegem F (2016) Ryanodine receptors under the magnifying lens: insights and limitations of cryo-electron microscopy and X-ray crystallography studies. Cell Calcium 59:209–227

    Article  CAS  PubMed  Google Scholar 

  79. Berridge MJ (2002) The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32:235–249

    Article  CAS  PubMed  Google Scholar 

  80. Tung CC, Lobo PA, Kimlicka L, Van Petegem F (2010) The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule. Nature 468:585–588

    Article  CAS  PubMed  Google Scholar 

  81. Amador FJ, Liu S, Ishiyama N, Plevin MJ, Wilson A, MacLennan DH, Ikura M (2009) Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation “hot spot” loop. Proc Natl Acad Sci USA 106:11040–11044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Amador FJ, Stathopulos PB, Enomoto M, Ikura M (2013) Ryanodine receptor calcium release channels: lessons from structure-function studies. Febs J 280:5456–5470

    Article  CAS  PubMed  Google Scholar 

  83. Bultynck G, Rossi D, Callewaert G, Missiaen L, Sorrentino V, Parys JB, De Smedt H (2001) The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different. J Biol Chem 276:47715–47724

    Article  CAS  PubMed  Google Scholar 

  84. Seo MD, Enomoto M, Ishiyama N, Stathopulos PB, Ikura M (2014) Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim Biophys Acta 1853(9):1980–1991

    Article  CAS  PubMed  Google Scholar 

  85. Straub SV, Giovannucci DR, Yule DI (2000) Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5-trisphosphate receptors, ryanodine receptors, and mitochondria. J Gen Physiol 116:547–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yuchi Z, Van Petegem F (2011) Common allosteric mechanisms between ryanodine and inositol-1,4,5-trisphosphate receptors. Channels (Austin) 5:120–123

    Article  CAS  Google Scholar 

  87. Amador FJ, Kimlicka L, Stathopulos PB, Gasmi-Seabrook GM, Maclennan DH, Van Petegem F, Ikura M (2013) Type 2 ryanodine receptor domain A contains a unique and dynamic alpha-helix that transitions to a beta-strand in a mutant linked with a heritable cardiomyopathy. J Mol Biol 425:4034–4046

    Article  CAS  PubMed  Google Scholar 

  88. Stathopulos PB, Seo MD, Enomoto M, Amador FJ, Ishiyama N, Ikura M (2012) Themes and variations in ER/SR calcium release channels: structure and function. Physiology 27:331–342

    Article  CAS  PubMed  Google Scholar 

  89. Fan G, Baker ML, Wang Z, Baker MR, Sinyagovskiy PA, Chiu W, Ludtke SJ, Serysheva II (2015) Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature 527:336–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hamada K, Miyatake H, Terauchi A, Mikoshiba K (2017) IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography. Proc Natl Acad Sci USA 114(18):4661–4666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Uchida K, Miyauchi H, Furuichi T, Michikawa T, Mikoshiba K (2003) Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 278:16551–16560

    Article  CAS  PubMed  Google Scholar 

  92. Schug ZT, Joseph SK (2006) The role of the S4-S5 linker and C-terminal tail in inositol 1,4,5-trisphosphate receptor function. J Biol Chem 281:24431–24440

    Article  CAS  PubMed  Google Scholar 

  93. Alzayady KJ, Wagner LE 2nd, Chandrasekhar R, Monteagudo A, Godiska R, Tall GG, Joseph SK, Yule DI (2013) Functional inositol 1,4,5-trisphosphate receptors assembled from concatenated homo- and heteromeric subunits. J Biol Chem 288:29772–29784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Alzayady KJ, Wang L, Chandrasekhar R, Wagner LE 2nd, Van Petegem F, Yule DI (2016) Defining the stoichiometry of inositol 1,4,5-trisphosphate binding required to initiate Ca2+ release. Sci Signal 9:ra35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chandrasekhar R, Alzayady KJ, Wagner LE 2nd, Yule DI (2016) Unique regulatory properties of heterotetrameric inositol 1,4,5-trisphosphate receptors revealed by studying concatenated receptor constructs. J Biol Chem 291:4846–4860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chandrasekhar R, Alzayady KJ, Yule DI (2015) Using concatenated subunits to investigate the functional consequences of heterotetrameric inositol 1,4,5-trisphosphate receptors. Biochem Soc Trans 43:364–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Berridge MJ (2009) Inositol trisphosphate and calcium signalling mechanisms. Biochim Biophys Acta 1793:933–940

    Article  CAS  PubMed  Google Scholar 

  98. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M (2006) Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: an initiation mechanism for capacitive Ca2+ entry. J Biol Chem 281:35855–35862

    Article  CAS  PubMed  Google Scholar 

  100. Zheng L, Stathopulos PB, Li GY, Ikura M (2008) Biophysical characterization of the EF-hand and SAM domain containing Ca2+ sensory region of STIM1 and STIM2. Biochem Biophys Res Commun 369:240–246

    Article  CAS  PubMed  Google Scholar 

  101. Stathopulos PB, Zheng L, Ikura M (2009) Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem 284:728–732

    Article  CAS  PubMed  Google Scholar 

  102. Zheng L, Stathopulos PB, Schindl R, Li GY, Romanin C, Ikura M (2011) Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc Natl Acad Sci USA 108:1337–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Manji SS, Parker NJ, Williams RT, van Stekelenburg L, Pearson RB, Dziadek M, Smith PJ (2000) STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta 1481:147–155

    Article  CAS  PubMed  Google Scholar 

  104. Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS, Shandala T, Saint R, Smith PJ, Dziadek MA (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J 357:673–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Williams RT, Senior PV, Van Stekelenburg L, Layton JE, Smith PJ, Dziadek MA (2002) Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim Biophys Acta 1596:131–137

    Article  CAS  PubMed  Google Scholar 

  106. Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M, Kurosaki T (2006) Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc Natl Acad Sci USA 103:16704–16709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Navarro-Borelly L, Somasundaram A, Yamashita M, Ren D, Miller RJ, Prakriya M (2008) STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J Physiol 586:5383–5401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Korzeniowski MK, Manjarres IM, Varnai P, Balla T (2010) Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci Signal 3:ra82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Muik M, Fahrner M, Schindl R, Stathopulos P, Frischauf I, Derler I, Plenk P, Lackner B, Groschner K, Ikura M, Romanin C (2011) STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation. EMBO J 30:1678–1689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yu F, Sun L, Hubrack S, Selvaraj S, Machaca K (2013) Intramolecular shielding maintains the ER Ca2+ sensor STIM1 in an inactive conformation. J Cell Sci 126:2401–2410

    Article  CAS  PubMed  Google Scholar 

  112. Zheng H, Zhou MH, Hu C, Kuo E, Peng X, Hu J, Kuo L, Zhang SL (2013) Differential roles of the C and N termini of Orai1 protein in interacting with stromal interaction molecule 1 (STIM1) for Ca2+ release-activated Ca2+ (CRAC) channel activation. J Biol Chem 288:11263–11272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M (2008) Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135:110–122

    Article  CAS  PubMed  Google Scholar 

  114. Huang Y, Zhou Y, Wong HC, Chen Y, Wang S, Castiblanco A, Liu A, Yang JJ (2009) A single EF-hand isolated from STIM1 forms dimer in the absence and presence of Ca2+. Febs J 276:5589–5597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cai X (2007) Molecular evolution and functional divergence of the Ca2+ sensor protein in store-operated Ca2+ entry: stromal interaction molecule. PLoS One 2:e609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bird GS, Hwang SY, Smyth JT, Fukushima M, Boyles RR, Putney JW Jr (2009) STIM1 is a calcium sensor specialized for digital signaling. Curr Biol 19:1724–1729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131:1327–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhou Y, Mancarella S, Wang Y, Yue C, Ritchie M, Gill DL, Soboloff J (2009) The short N-terminal domains of STIM1 and STIM2 control the activation kinetics of Orai1 channels. J Biol Chem 284:19164–19168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gruszczynska-Biegala J, Pomorski P, Wisniewska MB, Kuznicki J (2011) Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. PLoS One 6:e19285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Choi YJ, Zhao Y, Bhattacharya M, Stathopulos PB (2017) Structural perturbations induced by Asn131 and Asn171 glycosylation converge within the EFSAM core and enhance stromal interaction molecule-1 mediated store operated calcium entry. Biochim Biophys Acta 1864:1054–1063

    Article  CAS  PubMed  Google Scholar 

  121. Kilch T, Alansary D, Peglow M, Dorr K, Rychkov G, Rieger H, Peinelt C, Niemeyer BA (2013) Mutations of the Ca2+-sensing stromal interaction molecule STIM1 regulate Ca2+ influx by altered oligomerization of STIM1 and by destabilization of the Ca2+ channel Orai1. J Biol Chem 288:1653–1664

    Article  CAS  PubMed  Google Scholar 

  122. Hawkins BJ, Irrinki KM, Mallilankaraman K, Lien YC, Wang Y, Bhanumathy CD, Subbiah R, Ritchie MF, Soboloff J, Baba Y, Kurosaki T, Joseph SK, Gill DL, Madesh M (2010) S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J Cell Biol 190:391–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Prins D, Groenendyk J, Touret N, Michalak M (2011) Modulation of STIM1 and capacitative Ca2+ entry by the endoplasmic reticulum luminal oxidoreductase ERp57. EMBO Rep 12:1182–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Liou J, Fivaz M, Inoue T, Meyer T (2007) Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci USA 104:9301–9306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Carafoli E, Krebs J (2016) Why calcium? How calcium became the best communicator. J Biol Chem 291:20849–20857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Marshall CB, Nishikawa T, Osawa M, Stathopulos PB, Ikura M (2015) Calmodulin and STIM proteins: two major calcium sensors in the cytoplasm and endoplasmic reticulum. Biochem Biophys Res Commun 460:5–21

    Article  CAS  PubMed  Google Scholar 

  127. Nakayama S, Kretsinger RH (1994) Evolution of the EF-hand family of proteins. Annu Rev Biophys Biomol Struct 23:473–507

    Article  CAS  PubMed  Google Scholar 

  128. Kim CA, Bowie JU (2003) SAM domains: uniform structure, diversity of function. Trends Biochem Sci 28:625–628

    Article  CAS  PubMed  Google Scholar 

  129. Kim CA, Phillips ML, Kim W, Gingery M, Tran HH, Robinson MA, Faham S, Bowie JU (2001) Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression. EMBO J 20:4173–4182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mercurio FA, Leone M (2016) The Sam domain of EphA2 receptor and its relevance to cancer: a novel challenge for drug discovery? Curr Med Chem 23:4718–4734

    Article  CAS  PubMed  Google Scholar 

  131. Stapleton D, Balan I, Pawson T, Sicheri F (1999) The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nat Struct Biol 6:44–49

    Article  CAS  PubMed  Google Scholar 

  132. Thanos CD, Goodwill KE, Bowie JU (1999) Oligomeric structure of the human EphB2 receptor SAM domain. Science 283:833–836

    Article  CAS  PubMed  Google Scholar 

  133. Qiao F, Bowie JU (2005) The many faces of SAM. Sci STKE 2005:re7

    PubMed  Google Scholar 

  134. Csutora P, Peter K, Kilic H, Park KM, Zarayskiy V, Gwozdz T, Bolotina VM (2008) Novel role for STIM1 as a trigger for calcium influx factor production. J Biol Chem 283:14524–14531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Czyz A, Brutkowski W, Fronk J, Duszynski J, Zablocki K (2009) Tunicamycin desensitizes store-operated Ca2+ entry to ATP and mitochondrial potential. Biochem Biophys Res Commun 381:176–180

    Article  CAS  PubMed  Google Scholar 

  136. Mignen O, Thompson JL, Shuttleworth TJ (2007) STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane. J Physiol 579:703–715

    Article  CAS  PubMed  Google Scholar 

  137. Cui B, Yang X, Li S, Lin Z, Wang Z, Dong C, Shen Y (2013) The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1. PLoS One 8:e74735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Maruyama Y, Ogura T, Mio K, Kato K, Kaneko T, Kiyonaka S, Mori Y, Sato C (2009) Tetrameric Orai1 is a teardrop-shaped molecule with a long, tapered cytoplasmic domain. J Biol Chem 284:13676–13685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Luik RM, Wu MM, Buchanan J, Lewis RS (2006) The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174:815–825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wu MM, Buchanan J, Luik RM, Lewis RS (2006) Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174:803–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11:337–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kawasaki T, Lange I, Feske S (2009) A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385:49–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yang X, Jin H, Cai X, Li S, Shen Y (2012) Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109:5657–5662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M (2013) STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. Nat Commun 4:2963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, Stathopulos PB, Ikura M, Rao A, Hogan PG (2013) Initial activation of STIM1, the regulator of store-operated calcium entry. Nat Struct Mol Biol 20:973–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Cai X (2007) Molecular evolution and structural analysis of the Ca(2+) release-activated Ca(2+) channel subunit, Orai. J Mol Biol 368:1284–1291

    Article  CAS  PubMed  Google Scholar 

  147. Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD (2008) The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456:116–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Thompson JL, Shuttleworth TJ (2013) How many Orai’s does it take to make a CRAC channel? Sci Rep 3:1961

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y, Chen Y, Hille B, Xu T, Chen L (2008) Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci USA 105:13668–13673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hou X, Pedi L, Diver MM, Long SB (2012) Crystal structure of the calcium release-activated calcium channel Orai. Science 338:1308–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Covington ED, Wu MM, Lewis RS (2010) Essential role for the CRAC activation domain in store-dependent oligomerization of STIM1. Mol Biol Cell 21:1897–1907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C (2009) A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J Biol Chem 284:8421–8426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C (2008) Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283:8014–8022

    Article  CAS  PubMed  Google Scholar 

  154. Bhardwaj R, Muller HM, Nickel W, Seedorf M (2013) Oligomerization and Ca2+/calmodulin control binding of the ER Ca2+-sensors STIM1 and STIM2 to plasma membrane lipids. Biosci Rep 33(5). https://doi.org/10.1042/BSR20130089

  155. Maleth J, Choi S, Muallem S, Ahuja M (2014) Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating. Nat Commun 5:5843

    Article  PubMed  PubMed Central  Google Scholar 

  156. Calloway N, Owens T, Corwith K, Rodgers W, Holowka D, Baird B (2011) Stimulated association of STIM1 and Orai1 is regulated by the balance of PtdIns(4,5)P(2) between distinct membrane pools. J Cell Sci 124:2602–2610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Korzeniowski MK, Popovic MA, Szentpetery Z, Varnai P, Stojilkovic SS, Balla T (2009) Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. J Biol Chem 284:21027–21035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Walsh CM, Chvanov M, Haynes LP, Petersen OH, Tepikin AV, Burgoyne RD (2009) Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry. Biochem J 425:159–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Frischauf I, Muik M, Derler I, Bergsmann J, Fahrner M, Schindl R, Groschner K, Romanin C (2009) Molecular determinants of the coupling between STIM1 and Orai channels: differential activation of Orai1-3 channels by a STIM1 coiled-coil mutant. J Biol Chem 284:21696–21706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lis A, Zierler S, Peinelt C, Fleig A, Penner R (2010) A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J Gen Physiol 136:673–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG (2010) STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nat Struct Mol Biol 17:112–116

    Article  CAS  PubMed  Google Scholar 

  163. Stathopulos PB, Ikura M (2013) Structural aspects of calcium-release activated calcium channel function. Channels (Austin) 7:344–353

    Article  CAS  Google Scholar 

  164. Martell JD, Deerinck TJ, Sancak Y, Poulos TL, Mootha VK, Sosinsky GE, Ellisman MH, Ting AY (2012) Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat Biotechnol 30:1143–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Deluca HF, Engstrom GW (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci USA 47:1744–1750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364

    Article  CAS  PubMed  Google Scholar 

  167. Prentki M, Janjic D, Wollheim CB (1983) The regulation of extramitochondrial steady state free Ca2+ concentration by rat insulinoma mitochondria. J Biol Chem 258:7597–7602

    CAS  PubMed  Google Scholar 

  168. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera – a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  PubMed  Google Scholar 

  169. Oxenoid K, Dong Y, Cao C, Cui T, Sancak Y, Markhard AL, Grabarek Z, Kong L, Liu Z, Ouyang B, Cong Y, Mootha VK, Chou JJ (2016) Architecture of the mitochondrial calcium uniporter. Nature 533:269–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Cao C, Wang S, Cui T, Su XC, Chou JJ (2017) Ion and inhibitor binding of the double-ring ion selectivity filter of the mitochondrial calcium uniporter. Proc Natl Acad Sci USA 114:E2846–E2851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lunin VV, Dobrovetsky E, Khutoreskaya G, Zhang R, Joachimiak A, Doyle DA, Bochkarev A, Maguire ME, Edwards AM, Koth CM (2006) Crystal structure of the CorA Mg2+ transporter. Nature 440:833–837

    Article  CAS  PubMed  Google Scholar 

  172. Lee SK, Shanmughapriya S, Mok MC, Dong Z, Tomar D, Carvalho E, Rajan S, Junop MS, Madesh M, Stathopulos PB (2016) Structural insights into mitochondrial calcium uniporter regulation by divalent cations. Cell Chem Biol 23:1157–1169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Dong Z, Shanmughapriya S, Tomar D, Siddiqui N, Lynch S, Nemani N, Breves SL, Zhang X, Tripathi A, Palaniappan P, Riitano MF, Worth AM, Seelam A, Carvalho E, Subbiah R, Jana F, Soboloff J, Peng Y, Cheung JY, Joseph SK, Caplan J, Rajan S, Stathopulos PB, Madesh M (2017) Mitochondrial Ca2+ uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity. Mol Cell 65:1014–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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 do H, Eom SH (2015) Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep 16:1318–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Favaron M, Bernardi P (1985) Tissue-specific modulation of the mitochondrial calcium uniporter by magnesium ions. FEBS Lett 183:260–264

    Article  CAS  PubMed  Google Scholar 

  176. Jung DW, Apel L, Brierley GP (1990) Matrix free Mg2+ changes with metabolic state in isolated heart mitochondria. Biochemistry 29:4121–4128

    Article  CAS  PubMed  Google Scholar 

  177. Moreau B, Parekh AB (2008) Ca2+ -dependent inactivation of the mitochondrial Ca2+ uniporter involves proton flux through the ATP synthase. Curr Biol 18:855–859

    Article  CAS  PubMed  Google Scholar 

  178. Szanda G, Rajki A, Gallego-Sandin S, Garcia-Sancho J, Spat A (2009) Effect of cytosolic Mg2+ on mitochondrial Ca2+ signaling. Pflugers Arch 457:941–954

    Article  CAS  PubMed  Google Scholar 

  179. Joiner ML, Koval OM, Li J, He BJ, Allamargot C, Gao Z, Luczak ED, Hall DD, Fink BD, Chen B, Yang J, Moore SA, Scholz TD, Strack S, Mohler PJ, Sivitz WI, Song LS, Anderson ME (2012) CaMKII determines mitochondrial stress responses in heart. Nature 491:269–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Bootman MD (2012) Calcium signaling. Cold Spring Harb Perspect Biol 4:a011171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bootman MD, Berridge MJ (1995) The elemental principles of calcium signaling. Cell 83:675–678

    Article  CAS  PubMed  Google Scholar 

  182. Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351:751–754

    Article  CAS  PubMed  Google Scholar 

  183. Tu H, Wang Z, Bezprozvanny I (2005) Modulation of mammalian inositol 1,4,5-trisphosphate receptor isoforms by calcium: a role of calcium sensor region. Biophys J 88:1056–1069

    Article  CAS  PubMed  Google Scholar 

  184. Wingard JN, Chan J, Bosanac I, Haeseleer F, Palczewski K, Ikura M, Ames JB (2005) Structural analysis of Mg2+ and Ca2+ binding to CaBP1, a neuron-specific regulator of calcium channels. J Biol Chem 280:37461–37470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Stathopulos PB, Ikura M (2009) Structurally delineating stromal interaction molecules as the endoplasmic reticulum calcium sensors and regulators of calcium release-activated calcium entry. Immunol Rev 231:113–131

    Article  CAS  PubMed  Google Scholar 

  186. Stathopulos PB, Ikura M (2010) Partial unfolding and oligomerization of stromal interaction molecules as an initiation mechanism of store operated calcium entry. Biochem Cell Biol 88:175–183

    Article  CAS  PubMed  Google Scholar 

  187. Stathopulos PB, Ikura M (2013) Structure and function of endoplasmic reticulum STIM calcium sensors. Curr Top Membr 71:59–93

    Article  CAS  PubMed  Google Scholar 

  188. Bauer MC, O’Connell D, Cahill DJ, Linse S (2008) Calmodulin binding to the polybasic C-termini of STIM proteins involved in store-operated calcium entry. Biochemistry 47:6089–6091

    Article  CAS  PubMed  Google Scholar 

  189. Liu Y, Zheng X, Mueller GA, Sobhany M, DeRose EF, Zhang Y, London RE, Birnbaumer L (2012) Crystal structure of calmodulin binding domain of orai1 in complex with Ca2+ calmodulin displays a unique binding mode. J Biol Chem 287:43030–43041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Mullins FM, Park CY, Dolmetsch RE, Lewis RS (2009) STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels. Proc Natl Acad Sci USA 106:15495–15500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Dubois C, Prevarskaya N, Vanden Abeele F (2016) The calcium-signaling toolkit: updates needed. Biochim Biophys Acta 1863:1337–1343

    Article  CAS  PubMed  Google Scholar 

  192. Marchadier E, Oates ME, Fang H, Donoghue PC, Hetherington AM, Gough J (2016) Evolution of the calcium-based intracellular signaling system. Genome Biol Evol 8:2118–2132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Schwaller B (2012) The regulation of a cell’s Ca2+ signaling toolkit: the Ca2+ homeostasome. Adv Exp Med Biol 740:1–25

    Article  CAS  PubMed  Google Scholar 

  194. Zampese E, Pizzo P (2012) Intracellular organelles in the saga of Ca2+ homeostasis: different molecules for different purposes? Cell Mol Life Sci 69:1077–1104

    Article  CAS  PubMed  Google Scholar 

  195. Glitsch M (2011) Protons and Ca2+: ionic allies in tumor progression? Physiology 26:252–265

    Article  CAS  PubMed  Google Scholar 

  196. Huang WC, Swietach P, Vaughan-Jones RD, Ansorge O, Glitsch MD (2008) Extracellular acidification elicits spatially and temporally distinct Ca2+ signals. Curr Biol 18:781–785

    Article  CAS  PubMed  Google Scholar 

  197. Wei WC, Jacobs B, Becker EB, Glitsch MD (2015) Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca2+ and H. Proc Natl Acad Sci USA 112:10738–10743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) 05239 (to P.B.S.), Canadian Institutes of Health Research (CIHR) MOP-13552 (to M.I.), NSERC UT393093 (to M.I.) and an Ontario Graduate Scholarship (to N.S.). M.I. holds the Canada Research Chair in Cancer Structural Biology.

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Authors and Affiliations

  1. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada

    Masahiro Enomoto, Tadateru Nishikawa & Mitsuhiko Ikura

  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Masahiro Enomoto, Tadateru Nishikawa & Mitsuhiko Ikura

  3. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada

    Naveed Siddiqui, Steve Chung & Peter B. Stathopulos

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  1. Masahiro Enomoto
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Correspondence to Mitsuhiko Ikura or Peter B. Stathopulos .

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  1. MPI for Biophysical Chemistry, Göttingen, Germany

    Joachim Krebs

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Enomoto, M., Nishikawa, T., Siddiqui, N., Chung, S., Ikura, M., Stathopulos, P.B. (2017). From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation. In: Krebs, J. (eds) Membrane Dynamics and Calcium Signaling. Advances in Experimental Medicine and Biology, vol 981. Springer, Cham. https://doi.org/10.1007/978-3-319-55858-5_10

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