The STIM-Orai Pathway: The Interactions Between STIM and Orai

  • Marc FahrnerEmail author
  • Rainer Schindl
  • Martin Muik
  • Isabella Derler
  • Christoph RomaninEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


A primary Ca2+ entry pathway in non-excitable cells is established by the Ca2+ release-activated Ca2+ channels. Their two limiting molecular components include the Ca2+-sensor protein STIM1 located in the endoplasmic reticulum and the Orai channel in the plasma membrane. STIM1 senses the luminal Ca2+ content, and store depletion induces its oligomerization into puncta-like structures, thereby triggering coupling to as well as activation of Orai channels. A C-terminal STIM1 domain is assumed to couple to both C- and N-terminal, cytosolic strands of Orai, accomplishing gating of the channel. Here we highlight the inter- and intramolecular steps of the STIM1-Orai signaling cascade together with critical sites of the pore structure that accomplishes Ca2+ permeation.


STIM-Orai coupling STIM oligomerization Orai nexus Orai activation Orai pore 



This work was supported by the Austrian Science Fund projects P28123 (to MF), P26067 (to RS), P28498 (to MM), P25210 as well as P27641 (to ID), and P27263 (to CR).


  1. Baba Y, Hayashit 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 U S A 103:16704–16709PubMedPubMedCentralCrossRefGoogle Scholar
  2. Baba Y, Nishida K, Fujii Y, Hirano T, Hikida M, Kurosaki T (2008) Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses. Nat Immunol 9:81–88PubMedCrossRefGoogle Scholar
  3. Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A, Samelson LE (2008) Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol Biol Cell 19:2802–2817PubMedPubMedCentralCrossRefGoogle Scholar
  4. Beck A, Fleig A, Penner R, Peinelt C (2014) Regulation of endogenous and heterologous Ca(2)(+) release-activated Ca(2)(+) currents by pH. Cell Calcium 56:235–243PubMedPubMedCentralCrossRefGoogle Scholar
  5. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca(2+) levels. Cell 131:1327–1339PubMedPubMedCentralCrossRefGoogle Scholar
  6. Cai X, Zhou Y, Nwokonko RM, Loktionova NA, Wang X, Xin P, Trebak M, Wang Y, Gill DL (2016) The Orai1 store-operated calcium channel functions as a hexamer. J Biol Chem 291:25764–25775PubMedCrossRefGoogle Scholar
  7. Calloway N, Vig M, Kinet JP, Holowka D, Baird B (2009) Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca2+ stores and on electrostatic interactions. Mol Biol Cell 20:389–399PubMedPubMedCentralCrossRefGoogle Scholar
  8. Covington ED, Wu MM, Lewis RS (2010) Essential role for the CRAC activation domain in store-dependent oligomerization of STIM1. Mol Biol Cell 21:1897–1907PubMedPubMedCentralCrossRefGoogle Scholar
  9. De Haven WI, Smyth JT, Boyles RR, Putney JW Jr (2007) Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem 282:17548–17556CrossRefGoogle Scholar
  10. Demuro A, Penna A, Safrina O, Yeromin AV, Amcheslavsky A, Cahalan MD, Parker I (2011) Subunit stoichiometry of human Orai1 and Orai3 channels in closed and open states. Proc Natl Acad Sci U S A 108:17832–17837PubMedPubMedCentralCrossRefGoogle Scholar
  11. Derler I, Fahrner M, Carugo O, Muik M, Bergsmann J, Schindl R, Frischauf I, Eshaghi S, Romanin C (2009) Increased hydrophobicity at the N terminus/membrane interface impairs gating of the severe combined immunodeficiency-related ORAI1 mutant. J Biol Chem 284:15903–15915PubMedPubMedCentralCrossRefGoogle Scholar
  12. Derler I, Plenk P, Fahrner M, Muik M, Jardin I, Schindl R, Gruber HJ, Groschner K, Romanin C (2013) The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. J Biol Chem 288:29025–29034PubMedPubMedCentralCrossRefGoogle Scholar
  13. Derler I, Jardin I, Stathopulos PB, Muik M, Fahrner M, Zayats V, Pandey SK, Poteser M, Lackner B, Absolonova M, Schindl R, Groschner K, Ettrich R, Ikura M, Romanin C (2016) Cholesterol modulates Orai1 channel function. Sci Signal 9:ra10PubMedPubMedCentralCrossRefGoogle Scholar
  14. Dong H, Sharma M, Zhou HX, Cross TA (2012) Glycines: role in alpha-helical membrane protein structures and a potential indicator of native conformation. Biochemistry 51:4779–4789PubMedPubMedCentralCrossRefGoogle Scholar
  15. Dong H, Fiorin G, Carnevale V, Treptow W, Klein ML (2013) Pore waters regulate ion permeation in a calcium release-activated calcium channel. Proc Natl Acad Sci U S A 110:17332–17337PubMedPubMedCentralCrossRefGoogle Scholar
  16. Dubois C, Vanden Abeele F, Lehen’kyi V, Gkika D, Guarmit B, Lepage G, Slomianny C, Borowiec AS, Bidaux G, Benahmed M, Shuba Y, Prevarskaya N (2014) Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer. Cancer Cell 26:19–32PubMedCrossRefGoogle Scholar
  17. Endo Y, Noguchi S, Hara Y, Hayashi YK, Motomura K, Miyatake S, Murakami N, Tanaka S, Yamashita S, Kizu R, Bamba M, Goto Y, Matsumoto N, Nonaka I, Nishino I (2015) Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca(2)(+) channels. Hum Mol Genet 24:637–648PubMedCrossRefGoogle Scholar
  18. Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C (2009) Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231:99–112PubMedCrossRefGoogle Scholar
  19. Fahrner M, Muik M, Schindl R, Butorac C, Stathopulos P, Zheng L, Jardin I, Ikura M, Romanin C (2014) A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). J Biol Chem 289:33231–33244PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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 441:179–185PubMedCrossRefGoogle Scholar
  21. 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 284:21696–21706PubMedPubMedCentralCrossRefGoogle Scholar
  22. Frischauf I, Zayats V, Deix M, Hochreiter A, Jardin I, Muik M, Lackner B, Svobodova B, Pammer T, Litvinukova M, Sridhar AA, Derler I, Bogeski I, Romanin C, Ettrich RH, Schindl R (2015) A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca(2+) permeation and SOCE-induced gene transcription. Sci Signal 8:ra131PubMedPubMedCentralCrossRefGoogle Scholar
  23. Grigoriev I, Gouveia SM, van der Vaart B, Demmers J, Smyth JT, Honnappa S, Splinter D, Steinmetz MO, Putney JW Jr, Hoogenraad CC, Akhmanova A (2008) STIM1 is a MT-plus-end-tracking protein involved in remodeling of the ER. Curr Biol 18:177–182PubMedPubMedCentralCrossRefGoogle Scholar
  24. Gudlur A, Quintana A, Zhou Y, Hirve N, Mahapatra S, Hogan PG (2014) STIM1 triggers a gating rearrangement at the extracellular mouth of the ORAI1 channel. Nat Commun 5:5164PubMedPubMedCentralCrossRefGoogle Scholar
  25. Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A (2007) Biochemical and functional characterization of Orai proteins. J Biol Chem 282:16232–16243PubMedCrossRefGoogle Scholar
  26. He L, Zhang Y, Ma G, Tan P, Li Z, Zang S, Wu X, Jing J, Fang S, Zhou L, Wang Y, Huang Y, Hogan PG, Han G, Zhou Y (2015) Near-infrared photoactivatable control of Ca(2+) signaling and optogenetic immunomodulation. Elife 4. doi: 10.7554/eLife.10024
  27. Honnappa S, Gouveia SM, Weisbrich A, Damberger FF, Bhavesh NS, Jawhari H, Grigoriev I, van Rijssel FJ, Buey RM, Lawera A, Jelesarov I, Winkler FK, Wuthrich K, Akhmanova A, Steinmetz MO (2009) An EB1-binding motif acts as a microtubule tip localization signal. Cell 138:366–376PubMedCrossRefGoogle Scholar
  28. Hoover PJ, Lewis RS (2011) Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci U S A 108:13299–13304PubMedPubMedCentralCrossRefGoogle Scholar
  29. Hou X, Pedi L, Diver MM, Long SB (2012) Crystal structure of the calcium release-activated calcium channel Orai. Science 338:1308–1313PubMedPubMedCentralCrossRefGoogle Scholar
  30. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF (2006) STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 8:1003–1010PubMedCrossRefGoogle Scholar
  31. Ishii T, Sato K, Kakumoto T, Miura S, Touhara K, Takeuchi S, Nakata T (2015) Light generation of intracellular Ca(2+) signals by a genetically encoded protein BACCS. Nat Commun 6:8021PubMedPubMedCentralCrossRefGoogle Scholar
  32. Jha A, Muallem S (2016) The CAR that drives Ca2+ to Orai1. Sci Signal 9:fs5PubMedCrossRefGoogle Scholar
  33. Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L, Shi X, Zhang SL, Zhong L, Huang Y, Dong MQ, Walker CL, Hogan PG, Wang Y, Zhou Y (2015) Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca(2)(+) influx. Nat Cell Biol 17:1339–1347PubMedPubMedCentralCrossRefGoogle Scholar
  34. 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 385:49–54PubMedPubMedCentralCrossRefGoogle Scholar
  35. Korzeniowski MK, Manjarres IM, Varnai P, Balla T (2010) Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci Signal 3:ra82PubMedPubMedCentralCrossRefGoogle Scholar
  36. Li Z, Lu J, Xu P, Xie X, Chen L, Xu T (2007) Mapping the interacting domains of STIM1 and Orai1 in Ca2+ release-activated Ca2+ channel activation. J Biol Chem 282:29448–29456PubMedCrossRefGoogle Scholar
  37. Li Z, Liu L, Deng Y, Ji W, Du W, Xu P, Chen L, Xu T (2011) Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res 21:305–315PubMedCrossRefGoogle Scholar
  38. 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 15:1235–1241PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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 U S A 104:9301–9306PubMedPubMedCentralCrossRefGoogle Scholar
  40. Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R (2007) CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol 17:794–800PubMedCrossRefGoogle Scholar
  41. 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 174:815–825PubMedPubMedCentralCrossRefGoogle Scholar
  42. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538–542PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ma G, Wei M, He L, Liu C, Wu B, Zhang SL, Jing J, Liang X, Senes A, Tan P, Li S, Sun A, Bi Y, Zhong L, Si H, Shen Y, Li M, Lee MS, Zhou W, Wang J, Wang Y, Zhou Y (2015) Inside-out Ca signalling prompted by STIM1 conformational switch. Nat Commun 6:7826PubMedPubMedCentralCrossRefGoogle Scholar
  44. Malli R, Naghdi S, Romanin C, Graier WF (2008) Cytosolic Ca2+ prevents the subplasmalemmal clustering of STIM1: an intrinsic mechanism to avoid Ca2+ overload. J Cell Sci 121:3133–3139PubMedPubMedCentralCrossRefGoogle Scholar
  45. 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 284:13676–13685PubMedPubMedCentralCrossRefGoogle Scholar
  46. McNally BA, Yamashita M, Engh A, Prakriya M (2009) Structural determinants of ion permeation in CRAC channels. Proc Natl Acad Sci U S A 106:22516–22521PubMedPubMedCentralCrossRefGoogle Scholar
  47. McNally BA, Somasundaram A, Yamashita M, Prakriya M (2012) Gated regulation of CRAC channel ion selectivity by STIM1. Nature 482:241–245PubMedPubMedCentralGoogle Scholar
  48. 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 281:24979–14990PubMedPubMedCentralCrossRefGoogle Scholar
  49. Mignen O, Thompson JL, Shuttleworth TJ (2008) Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol 586:419–425PubMedCrossRefGoogle Scholar
  50. Misceo D, Holmgren A, Louch WE, Holme PA, Mizobuchi M, Morales RJ, De Paula AM, Stray-Pedersen A, Lyle R, Dalhus B, Christensen G, Stormorken H, Tjonnfjord GE, Frengen E (2014) A dominant STIM1 mutation causes Stormorken syndrome. Hum Mutat 35:556–564PubMedCrossRefGoogle Scholar
  51. Morin G, Bruechle NO, Singh AR, Knopp C, Jedraszak G, Elbracht M, Bremond-Gignac D, Hartmann K, Sevestre H, Deutz P, Herent D, Nurnberg P, Romeo B, Konrad K, Mathieu-Dramard M, Oldenburg J, Bourges-Petit E, Shen Y, Zerres K, Ouadid-Ahidouch H, Rochette J (2014) Gain-of-Function mutation in STIM1 (p.R304W) is associated with Stormorken syndrome. Hum Mutat 35:1221–1232PubMedCrossRefGoogle Scholar
  52. 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 283:8014–8022PubMedCrossRefGoogle Scholar
  53. 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 284:8421–8426PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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 30:1678–1689PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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 586:5383–5401PubMedPubMedCentralCrossRefGoogle Scholar
  56. Nesin V, Wiley G, Kousi M, Ong EC, Lehmann T, Nicholl DJ, Suri M, Shahrizaila N, Katsanis N, Gaffney PM, Wierenga KJ, Tsiokas L (2014) Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci U S A 111:4197–4202PubMedPubMedCentralCrossRefGoogle Scholar
  57. Pacheco J, Dominguez L, Bohorquez-Hernandez A, Asanov A, Vaca L (2016) A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions. Sci Rep 6:29634PubMedPubMedCentralCrossRefGoogle Scholar
  58. Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E (2012) SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149:425–438PubMedCrossRefGoogle Scholar
  59. Palty R, Stanley C, Isacoff EY (2015) Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res 25:963–980PubMedPubMedCentralCrossRefGoogle Scholar
  60. Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85:757–810PubMedCrossRefGoogle Scholar
  61. 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 136:876–890PubMedPubMedCentralCrossRefGoogle Scholar
  62. Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771–773PubMedCrossRefGoogle Scholar
  63. 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 456:116–120PubMedPubMedCentralCrossRefGoogle Scholar
  64. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233PubMedCrossRefGoogle Scholar
  65. 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 169:435–445PubMedPubMedCentralCrossRefGoogle Scholar
  66. Saotome K, Singh AK, Yelshanskaya MV, Sobolevsky AI (2016) Crystal structure of the epithelial calcium channel TRPV6. Nature 534:506–511PubMedPubMedCentralCrossRefGoogle Scholar
  67. Schindl R, Bergsmann J, Frischauf I, Derler I, Fahrner M, Muik M, Fritsch R, Groschner K, Romanin C (2008) 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. J Biol Chem 283:20261–20267PubMedCrossRefGoogle Scholar
  68. Schindl R, Frischauf I, Bergsmann J, Muik M, Derler I, Lackner B, Groschner K, Romanin C (2009) Plasticity in Ca2+ selectivity of Orai1/Orai3 heteromeric channel. Proc Natl Acad Sci U S A 106:19623–19628PubMedPubMedCentralCrossRefGoogle Scholar
  69. Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY (2009) Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol 587:2903–2918PubMedPubMedCentralCrossRefGoogle Scholar
  70. Scrimgeour NR, Wilson DP, Barritt GJ, Rychkov GY (2014) Structural and stoichiometric determinants of Ca release-activated Ca (CRAC) channel Ca-dependent inactivation. Biochim Biophys Acta 1838:1281–1287PubMedCrossRefGoogle Scholar
  71. Sharma S, Quintana A, Findlay GM, Mettlen M, Baust B, Jain M, Nilsson R, Rao A, Hogan PG (2013) An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry. Nature 499:238–242PubMedCrossRefGoogle Scholar
  72. Smyth JT, Dehaven WI, Bird GS, Putney JW Jr (2008) Ca2+-store-dependent and -independent reversal of Stim1 localization and function. J Cell Sci 121:762–772PubMedPubMedCentralCrossRefGoogle Scholar
  73. Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL (2006) STIM2 is an inhibitor of STIM1-mediated store-operated Ca(2+) entry. Curr Biol 16:1465–1470PubMedCrossRefGoogle Scholar
  74. Soboloff J, Rothberg BS, Madesh M, Gill DL (2012) STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13:549–565PubMedPubMedCentralCrossRefGoogle Scholar
  75. Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge J, Gwack Y (2010) A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells. Nat Cell Biol 12:436–446PubMedPubMedCentralCrossRefGoogle Scholar
  76. 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 88:175–183PubMedCrossRefGoogle Scholar
  77. Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M (2006) Stored Ca2+ depletion-induced oligomerization of STIM1 via the EF-SAM region: an initiation mechanism for capacitive Ca2+ entry. J Biol Chem 281:35855–35862PubMedCrossRefGoogle Scholar
  78. 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 135:110–122PubMedCrossRefGoogle Scholar
  79. 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 4:2963PubMedPubMedCentralCrossRefGoogle Scholar
  80. Tirado-Lee L, Yamashita M, Prakriya M (2015) Conformational changes in the Orai1 C-terminus evoked by STIM1 binding. PLoS One 10:e0128622PubMedPubMedCentralCrossRefGoogle Scholar
  81. Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R (2006a) CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16:2073–2079PubMedCrossRefGoogle Scholar
  82. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006b) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223PubMedCrossRefGoogle Scholar
  83. Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL (2014) Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun 5:3183PubMedPubMedCentralGoogle Scholar
  84. 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 174:803–813PubMedPubMedCentralCrossRefGoogle Scholar
  85. Wu J, Yan Z, Li Z, Yan C, Lu S, Dong M, Yan N (2015) Structure of the voltage-gated calcium channel Cav1.1 complex. Science 350:aad2395PubMedCrossRefGoogle Scholar
  86. Xu P, Lu J, Li Z, Yu X, Chen L, Xu T (2006) Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1. Biochem Biophys Res Commun 350:969–976PubMedCrossRefGoogle Scholar
  87. Yamashita M, Yeung PS, Ing CI, McNally BA, Pomes R, Prakrya M (2017) STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate. Nat Commun. doi: 10.1038/ncomms14512 Google Scholar
  88. 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 U S A 109:5657–5662PubMedPubMedCentralCrossRefGoogle Scholar
  89. Yen M, Lokteva LA, Lewis RS (2016) Functional analysis of Orai1 concatemers supports a hexameric stoichiometry for the CRAC channel. Biophys J 111:1897–1907PubMedCrossRefGoogle Scholar
  90. 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 443:226–229PubMedPubMedCentralCrossRefGoogle Scholar
  91. Yeung PS, Yamashita M, Prakriya M (2016) Pore opening mechanism of CRAC channels. Cell Calcium. doi: 10.1016/j.ceca.2016.12.006 PubMedGoogle Scholar
  92. Yu F, Sun L, Hubrack S, Selvaraj S, Machaca K (2013) Intramolecular shielding maintains the ER Ca(2)(+) sensor STIM1 in an inactive conformation. J Cell Sci 126:2401–2410PubMedCrossRefGoogle Scholar
  93. 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 11:337–343PubMedPubMedCentralCrossRefGoogle Scholar
  94. Zalk R, Clarke OB, des Georges A, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR (2015) Structure of a mammalian ryanodine receptor. Nature 517:44–49PubMedCrossRefGoogle Scholar
  95. 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 437:902–905PubMedPubMedCentralCrossRefGoogle Scholar
  96. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (2006) Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activated Ca(2+) channel activity. Proc Natl Acad Sci U S A 103:9357–9362PubMedPubMedCentralCrossRefGoogle Scholar
  97. Zhang SL, Kozak JA, Jiang W, Yeromin AV, Chen J, Yu Y, Penna A, Shen W, Chi V, Cahalan MD (2008) Store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. J Biol Chem 283:17662–17671PubMedPubMedCentralCrossRefGoogle Scholar
  98. Zhang SL, Yeromin AV, Hu J, Amcheslavsky A, Zheng H, Cahalan MD (2011) Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proc Natl Acad Sci U S A 108:17838–17843PubMedPubMedCentralCrossRefGoogle Scholar
  99. Zhang W, Zhang X, Gonzalez-Cobos JC, Stolwijk JA, Matrougui K, Trebak M (2015) Leukotriene-C4 synthase, a critical enzyme in the activation of store-independent Orai1/Orai3 channels, is required for neointimal hyperplasia. J Biol Chem 290:5015–5027PubMedCrossRefGoogle 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 369:240–246PubMedCrossRefGoogle Scholar
  101. 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 U S A 108:1337–1342PubMedPubMedCentralCrossRefGoogle Scholar
  102. Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG (2010a) STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nat Struct Mol Biol 17:112–116PubMedCrossRefGoogle Scholar
  103. Zhou Y, Ramachandran S, Oh-Hora M, Rao A, Hogan PG (2010b) Pore architecture of the ORAI1 store-operated calcium channel. Proc Natl Acad Sci U S A 107:4896–4901PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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 20:973–981PubMedPubMedCentralCrossRefGoogle Scholar
  105. Zhou Y, Cai X, Loktionova NA, Wang X, Nwokonko RM, Wang X, Wang Y, Rothberg BS, Trebak M, Gill DL (2016) The STIM1-binding site nexus remotely controls Orai1 channel gating. Nat Commun 7:13725PubMedPubMedCentralCrossRefGoogle Scholar
  106. Zhou Y, Cai X, Nwokonko RM, Loktionova NA, Wang Y, Gill DL (2017) The STIM-Orai coupling interface and gating of the Orai1 channel. Cell Calcium. doi: 10.1016/j.ceca.2017.01.001 Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Institute of BiophysicsJohannes Kepler University LinzLinzAustria

Personalised recommendations