CRCM1_HUMAN
ID CRCM1_HUMAN Reviewed; 301 AA.
AC Q96D31; Q3MHV3; Q6DHX2; Q96BP7; Q96K71;
DT 16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 16-MAY-2006, sequence version 2.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Calcium release-activated calcium channel protein 1;
DE AltName: Full=Protein orai-1;
DE AltName: Full=Transmembrane protein 142A;
GN Name=ORAI1; Synonyms=CRACM1, TMEM142A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA), AND VARIANT
RP GLY-218.
RC TISSUE=Bone marrow, Ovary, Prostate, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-301 (ISOFORM ALPHA), AND
RP VARIANT GLY-218.
RC TISSUE=Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP INVOLVEMENT IN IMD9.
RX PubMed=16147976; DOI=10.1084/jem.20050687;
RA Feske S., Prakriya M., Rao A., Lewis R.S.;
RT "A severe defect in CRAC Ca2+ channel activation and altered K+ channel
RT gating in T cells from immunodeficient patients.";
RL J. Exp. Med. 202:651-662(2005).
RN [4]
RP FUNCTION.
RX PubMed=16766533; DOI=10.1074/jbc.c600126200;
RA Soboloff J., Spassova M.A., Tang X.D., Hewavitharana T., Xu W., Gill D.L.;
RT "Orai1 and STIM reconstitute store-operated calcium channel function.";
RL J. Biol. Chem. 281:20661-20665(2006).
RN [5]
RP FUNCTION.
RX PubMed=16807233; DOI=10.1074/jbc.m604589200;
RA Mercer J.C., Dehaven W.I., Smyth J.T., Wedel B., Boyles R.R., Bird G.S.,
RA Putney J.W. Jr.;
RT "Large store-operated calcium selective currents due to co-expression of
RT Orai1 or Orai2 with the intracellular calcium sensor, Stim1.";
RL J. Biol. Chem. 281:24979-24990(2006).
RN [6]
RP FUNCTION.
RX PubMed=16733527; DOI=10.1038/ncb1435;
RA Peinelt C., Vig M., Koomoa D.L., Beck A., Nadler M.J.S.,
RA Koblan-Huberson M., Lis A., Fleig A., Penner R., Kinet J.-P.;
RT "Amplification of CRAC current by STIM1 and CRACM1 (Orai1).";
RL Nat. Cell Biol. 8:771-773(2006).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16645049; DOI=10.1126/science.1127883;
RA Vig M., Peinelt C., Beck A., Koomoa D.L., Rabah D., Koblan-Huberson M.,
RA Kraft S., Turner H., Fleig A., Penner R., Kinet J.-P.;
RT "CRACM1 is a plasma membrane protein essential for store-operated Ca2+
RT entry.";
RL Science 312:1220-1223(2006).
RN [8]
RP INTERACTION WITH STIM1 AND STIM2.
RX PubMed=17905723; DOI=10.1096/fj.07-9449com;
RA Parvez S., Beck A., Peinelt C., Soboloff J., Lis A., Monteilh-Zoller M.,
RA Gill D.L., Fleig A., Penner R.;
RT "STIM2 protein mediates distinct store-dependent and store-independent
RT modes of CRAC channel activation.";
RL FASEB J. 22:752-761(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-295 AND SER-298, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP FUNCTION, INTERACTION WITH STIM1, SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT,
RP AND GLYCOSYLATION.
RX PubMed=19249086; DOI=10.1016/j.cell.2009.02.014;
RA Park C.Y., Hoover P.J., Mullins F.M., Bachhawat P., Covington E.D.,
RA Raunser S., Walz T., Garcia K.C., Dolmetsch R.E., Lewis R.S.;
RT "STIM1 clusters and activates CRAC channels via direct binding of a
RT cytosolic domain to Orai1.";
RL Cell 136:876-890(2009).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ATP2C2, AND MUTAGENESIS OF
RP LEU-273.
RX PubMed=20887894; DOI=10.1016/j.cell.2010.08.040;
RA Feng M., Grice D.M., Faddy H.M., Nguyen N., Leitch S., Wang Y., Muend S.,
RA Kenny P.A., Sukumar S., Roberts-Thomson S.J., Monteith G.R., Rao R.;
RT "Store-independent activation of Orai1 by SPCA2 in mammary tumors.";
RL Cell 143:84-98(2010).
RN [12]
RP INTERACTION WITH CRACR2A, AND MUTAGENESIS OF 85-LYS--LYS-87.
RX PubMed=20418871; DOI=10.1038/ncb2045;
RA Srikanth S., Jung H.J., Kim K.D., Souda P., Whitelegge J., Gwack Y.;
RT "A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that
RT stabilizes CRAC channels in T cells.";
RL Nat. Cell Biol. 12:436-446(2010).
RN [13]
RP FUNCTION, TISSUE SPECIFICITY, OXIDATION, AND MUTAGENESIS OF CYS-195.
RX PubMed=20354224; DOI=10.1126/scisignal.2000672;
RA Bogeski I., Kummerow C., Al-Ansary D., Schwarz E.C., Koehler R., Kozai D.,
RA Takahashi N., Peinelt C., Griesemer D., Bozem M., Mori Y., Hoth M.,
RA Niemeyer B.A.;
RT "Differential redox regulation of ORAI ion channels: a mechanism to tune
RT cellular calcium signaling.";
RL Sci. Signal. 3:RA24-RA24(2010).
RN [14]
RP INTERACTION WITH SLC35G1.
RX PubMed=22084111; DOI=10.1073/pnas.1117231108;
RA Krapivinsky G., Krapivinsky L., Stotz S.C., Manasian Y., Clapham D.E.;
RT "POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to
RT multiple transporters.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:19234-19239(2011).
RN [15]
RP ALTERNATIVE INITIATION, AND SUBCELLULAR LOCATION.
RX PubMed=22641696; DOI=10.1242/jcs.104919;
RA Fukushima M., Tomita T., Janoshazi A., Putney J.W.;
RT "Alternative translation initiation gives rise to two isoforms of orai1
RT with distinct plasma membrane mobilities.";
RL J. Cell Sci. 125:4354-4361(2012).
RN [16]
RP INTERACTION WITH ASPH.
RX PubMed=22586105; DOI=10.1073/pnas.1200667109;
RA Srikanth S., Jew M., Kim K.D., Yee M.K., Abramson J., Gwack Y.;
RT "Junctate is a Ca2+-sensing structural component of Orai1 and stromal
RT interaction molecule 1 (STIM1).";
RL Proc. Natl. Acad. Sci. U.S.A. 109:8682-8687(2012).
RN [17]
RP INTERACTION WITH ADCY8.
RX PubMed=22494970; DOI=10.1126/scisignal.2002299;
RA Willoughby D., Everett K.L., Halls M.L., Pacheco J., Skroblin P., Vaca L.,
RA Klussmann E., Cooper D.M.;
RT "Direct binding between Orai1 and AC8 mediates dynamic interplay between
RT Ca2+ and cAMP signaling.";
RL Sci. Signal. 5:RA29-RA29(2012).
RN [18]
RP FUNCTION, INTERACTION WITH UBQLN1, SUBCELLULAR LOCATION, UBIQUITINATION,
RP AND DEGRADATION VIA AUTOPHAGY.
RX PubMed=23307288; DOI=10.1007/s10059-013-2268-7;
RA Lee J.E., Jeon I.S., Han N.E., Song H.J., Kim E.G., Choi J.W., Song K.D.,
RA Lee H.K., Choi J.K.;
RT "Ubiquilin 1 interacts with Orai1 to regulate calcium mobilization.";
RL Mol. Cells 35:41-46(2013).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP FUNCTION, INVOLVEMENT IN TAM2, VARIANT TAM2 LEU-245, AND CHARACTERIZATION
RP OF VARIANT TAM2 LEU-245.
RX PubMed=24591628; DOI=10.1073/pnas.1312520111;
RA Nesin V., Wiley G., Kousi M., Ong E.C., Lehmann T., Nicholl D.J., Suri M.,
RA Shahrizaila N., Katsanis N., Gaffney P.M., Wierenga K.J., Tsiokas L.;
RT "Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of
RT tubular myopathy and congenital miosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:4197-4202(2014).
RN [21]
RP INTERACTION WITH STIM1, AND SUBCELLULAR LOCATION.
RX PubMed=27185316; DOI=10.1159/000445574;
RA Zhang L., Wang L., Li S., Xue J., Luo D.;
RT "Calsequestrin-1 regulates store-operated Ca2+ entry by inhibiting STIM1
RT aggregation.";
RL Cell. Physiol. Biochem. 38:2183-2193(2016).
RN [22]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION AT
RP ASN-223, AND MUTAGENESIS OF ASN-223.
RX PubMed=26956484; DOI=10.1126/scisignal.aaa9913;
RA Doerr K., Kilch T., Kappel S., Alansary D., Schwaer G., Niemeyer B.A.,
RA Peinelt C.;
RT "Cell type-specific glycosylation of Orai1 modulates store-operated Ca2+
RT entry.";
RL Sci. Signal. 9:RA25-RA25(2016).
RN [23]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH STIM1, OXIDATION, AND
RP MUTAGENESIS OF CYS-195.
RX PubMed=28219928; DOI=10.15252/embj.201592481;
RA Ben-Kasus Nissim T., Zhang X., Elazar A., Roy S., Stolwijk J.A., Zhou Y.,
RA Motiani R.K., Gueguinou M., Hempel N., Hershfinkel M., Gill D.L.,
RA Trebak M., Sekler I.;
RT "Mitochondria control store-operated Ca(2+) entry through Na(+) and redox
RT signals.";
RL EMBO J. 36:797-815(2017).
RN [24]
RP INTERACTION WITH EFHB AND STIM1.
RX PubMed=30481768; DOI=10.1159/000495494;
RA Albarran L., Lopez J.J., Jardin I., Sanchez-Collado J., Berna-Erro A.,
RA Smani T., Camello P.J., Salido G.M., Rosado J.A.;
RT "EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF
RT Interaction.";
RL Cell. Physiol. Biochem. 51:1164-1178(2018).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 69-88 IN COMPLEX WITH CALM, AND
RP INTERACTION WITH CALM.
RX PubMed=23109337; DOI=10.1074/jbc.m112.380964;
RA Liu Y., Zheng X., Mueller G.A., Sobhany M., DeRose E.F., Zhang Y.,
RA London R.E., Birnbaumer L.;
RT "Crystal structure of calmodulin binding domain of orai1 in complex with
RT Ca2+ calmodulin displays a unique binding mode.";
RL J. Biol. Chem. 287:43030-43041(2012).
RN [26]
RP STRUCTURE BY NMR OF 272-292 IN COMPLEX WITH STIM1, INTERACTION WITH STIM1,
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-281; ASP-284;
RP LEU-286; ASP-287; ARG-289 AND ASP-291.
RX PubMed=24351972; DOI=10.1038/ncomms3963;
RA Stathopulos P.B., Schindl R., Fahrner M., Zheng L., Gasmi-Seabrook G.M.,
RA Muik M., Romanin C., Ikura M.;
RT "STIM1/Orai1 coiled-coil interplay in the regulation of store-operated
RT calcium entry.";
RL Nat. Commun. 4:2963-2963(2013).
RN [27]
RP VARIANT IMD9 TRP-91, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=16582901; DOI=10.1038/nature04702;
RA Feske S., Gwack Y., Prakriya M., Srikanth S., Puppel S.-H., Tanasa B.,
RA Hogan P.G., Lewis R.S., Daly M., Rao A.;
RT "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel
RT function.";
RL Nature 441:179-185(2006).
RN [28]
RP VARIANTS TAM2 SER-98; MET-107 AND MET-184, AND SUBCELLULAR LOCATION.
RX PubMed=28058752; DOI=10.1002/humu.23172;
RA Boehm J., Bulla M., Urquhart J.E., Malfatti E., Williams S.G.,
RA O'Sullivan J., Szlauer A., Koch C., Baranello G., Mora M., Ripolone M.,
RA Violano R., Moggio M., Kingston H., Dawson T., DeGoede C.G., Nixon J.,
RA Boland A., Deleuze J.F., Romero N., Newman W.G., Demaurex N., Laporte J.;
RT "ORAI1 mutations with distinct channel gating defects in tubular aggregate
RT myopathy.";
RL Hum. Mutat. 38:426-438(2017).
CC -!- FUNCTION: Ca(2+) release-activated Ca(2+) (CRAC) channel subunit which
CC mediates Ca(2+) influx following depletion of intracellular Ca(2+)
CC stores and channel activation by the Ca(2+) sensor, STIM1
CC (PubMed:16582901, PubMed:16645049, PubMed:16733527, PubMed:16766533,
CC PubMed:16807233, PubMed:19249086, PubMed:23307288, PubMed:24351972,
CC PubMed:24591628, PubMed:28219928, PubMed:20354224, PubMed:26956484).
CC CRAC channels are the main pathway for Ca(2+) influx in T-cells and
CC promote the immune response to pathogens by activating the
CC transcription factor NFAT (PubMed:16582901). Plays a prominent role in
CC Ca(2+) influx at the basolateral membrane of mammary epithelial cells
CC independently of the Ca(2+) content of endoplasmic reticulum or Golgi
CC stores. May mediate transepithelial transport of large quantities of
CC Ca(2+) for milk secretion. {ECO:0000250|UniProtKB:Q8BWG9,
CC ECO:0000269|PubMed:16582901, ECO:0000269|PubMed:16645049,
CC ECO:0000269|PubMed:16733527, ECO:0000269|PubMed:16766533,
CC ECO:0000269|PubMed:16807233, ECO:0000269|PubMed:19249086,
CC ECO:0000269|PubMed:20354224, ECO:0000269|PubMed:20887894,
CC ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:24351972,
CC ECO:0000269|PubMed:24591628, ECO:0000269|PubMed:26956484,
CC ECO:0000269|PubMed:28219928}.
CC -!- ACTIVITY REGULATION: Oxidation at Cys-195 leads to inactivation of
CC channel activity. {ECO:0000269|PubMed:20354224,
CC ECO:0000269|PubMed:28219928}.
CC -!- SUBUNIT: Interacts with STIM1 and STIM2; this regulates channel
CC activity (PubMed:17905723, PubMed:19249086, PubMed:24351972,
CC PubMed:28219928, PubMed:27185316, PubMed:30481768). Interacts with
CC CALM; this may displace STIM1 and STIM2 and might thereby modulate
CC channel activity (PubMed:23109337). Interacts with CRACR2A/EFCAB4B; the
CC interaction is direct and takes place in absence of Ca(2+)
CC (PubMed:20418871). Forms a complex with CRACR2A/EFCAB4B and STIM1 at
CC low concentration of Ca(2+), the complex dissociates at elevated Ca(2+)
CC concentrations. Interacts with ASPH (isoform 8) (PubMed:22586105).
CC Interacts with SLC35G1 (PubMed:22084111). Interacts with UBQLN1
CC (PubMed:23307288). Interacts with ADCY8; interaction is calcium store
CC depletion independent; interaction occurs in membrane raft; interaction
CC increases markedly after store depletion; positively regulates SOCE-
CC induced adenylate cyclase activity; contributes to the targeting of
CC ADCY8 to discrete regions of the plasma membrane that are shielded from
CC other calcium events (PubMed:22494970). Interacts with EFHB; the
CC interaction takes place upon Ca(2+)-store depletion (PubMed:30481768).
CC Interacts (via N- and C-termini) with ATP2C2 (via N-terminus); this
CC interaction regulates Ca(2+) influx at the plasma membrane.
CC {ECO:0000269|PubMed:17905723, ECO:0000269|PubMed:19249086,
CC ECO:0000269|PubMed:20418871, ECO:0000269|PubMed:20887894,
CC ECO:0000269|PubMed:22084111, ECO:0000269|PubMed:22494970,
CC ECO:0000269|PubMed:22586105, ECO:0000269|PubMed:23109337,
CC ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:24351972,
CC ECO:0000269|PubMed:28219928, ECO:0000269|PubMed:30481768}.
CC -!- INTERACTION:
CC Q96D31; O75185: ATP2C2; NbExp=10; IntAct=EBI-2291476, EBI-2939806;
CC Q96D31; Q9BSW2: CRACR2A; NbExp=6; IntAct=EBI-2291476, EBI-739773;
CC Q96D31; Q8N7U6: EFHB; NbExp=2; IntAct=EBI-2291476, EBI-25602059;
CC Q96D31; Q96D31: ORAI1; NbExp=9; IntAct=EBI-2291476, EBI-2291476;
CC Q96D31; Q9BRQ5: ORAI3; NbExp=4; IntAct=EBI-2291476, EBI-4279484;
CC Q96D31; Q13586: STIM1; NbExp=21; IntAct=EBI-2291476, EBI-448878;
CC Q96D31; P48995: TRPC1; NbExp=2; IntAct=EBI-2291476, EBI-929665;
CC Q96D31; Q13507: TRPC3; NbExp=2; IntAct=EBI-2291476, EBI-520807;
CC Q96D31; P62161: Calm3; Xeno; NbExp=5; IntAct=EBI-2291476, EBI-397530;
CC Q96D31; Q61143: Trpc6; Xeno; NbExp=2; IntAct=EBI-2291476, EBI-15563578;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16582901,
CC ECO:0000269|PubMed:16645049, ECO:0000269|PubMed:19249086,
CC ECO:0000269|PubMed:20887894, ECO:0000269|PubMed:22641696,
CC ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:24351972,
CC ECO:0000269|PubMed:26956484, ECO:0000269|PubMed:27185316,
CC ECO:0000269|PubMed:28058752, ECO:0000269|PubMed:28219928}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:16582901,
CC ECO:0000269|PubMed:16645049, ECO:0000269|PubMed:19249086,
CC ECO:0000269|PubMed:22641696, ECO:0000269|PubMed:24351972}. Basolateral
CC cell membrane {ECO:0000250|UniProtKB:Q8BWG9}; Multi-pass membrane
CC protein {ECO:0000269|PubMed:19249086}. Note=Isoform beta is more mobile
CC in the plasma membrane (PubMed:23307288). Colocalizes with STIM1 at the
CC cell membrane (PubMed:27185316). {ECO:0000269|PubMed:23307288,
CC ECO:0000269|PubMed:27185316}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=alpha;
CC IsoId=Q96D31-1; Sequence=Displayed;
CC Name=beta;
CC IsoId=Q96D31-2; Sequence=VSP_044421;
CC -!- TISSUE SPECIFICITY: Expressed in naive CD4 and CD8 T cells (at protein
CC level) (PubMed:26956484). Expressed at similar levels in naive and
CC effector T helper cells (PubMed:20354224).
CC {ECO:0000269|PubMed:20354224, ECO:0000269|PubMed:26956484}.
CC -!- PTM: N-glycosylated (PubMed:19249086, PubMed:26956484). N-glycosylation
CC inhibits channel activity in T cells (PubMed:26956484).
CC {ECO:0000269|PubMed:19249086, ECO:0000269|PubMed:26956484}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:23307288}.
CC -!- PTM: Cys-195 is oxidated, leading to inactivation of channel activity.
CC {ECO:0000269|PubMed:20354224, ECO:0000269|PubMed:28219928}.
CC -!- DISEASE: Immunodeficiency 9 (IMD9) [MIM:612782]: An immune disorder
CC characterized by recurrent infections, impaired activation and
CC proliferative response of T-cells, decreased T-cell production of
CC cytokines, and normal lymphocytes counts and serum immunoglobulin
CC levels. In surviving patients ectodermal dysplasia with anhidrosis and
CC non-progressive myopathy may be observed. {ECO:0000269|PubMed:16147976,
CC ECO:0000269|PubMed:16582901}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Myopathy, tubular aggregate, 2 (TAM2) [MIM:615883]: A rare
CC congenital myopathy characterized by regular arrays of membrane tubules
CC on muscle biopsies without additional histopathological hallmarks.
CC Tubular aggregates in muscle are structures of variable appearance
CC consisting of an outer tubule containing either one or more
CC microtubule-like structures or amorphous material. TAM2 patients have
CC myopathy and pupillary abnormalities. {ECO:0000269|PubMed:24591628,
CC ECO:0000269|PubMed:28058752}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In Greek mythology, the 'Orai' are the keepers of the
CC gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene
CC (peace). {ECO:0000303|PubMed:16582901}.
CC -!- SIMILARITY: Belongs to the Orai family. {ECO:0000305}.
CC -!- CAUTION: According to a report, ORAI1 has been shown to colocalize with
CC UBQLN1 in the autophagosome as a target for autophagic degradation;
CC ORAI1 is however not an autophagosomal protein.
CC {ECO:0000269|PubMed:23307288}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH13386.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAI04634.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB55068.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=ORAI1base; Note=ORAI1 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/ORAI1base/";
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DR EMBL; BC013386; AAH13386.1; ALT_INIT; mRNA.
DR EMBL; BC015369; AAH15369.2; -; mRNA.
DR EMBL; BC075831; AAH75831.1; -; mRNA.
DR EMBL; BC104633; AAI04634.1; ALT_INIT; mRNA.
DR EMBL; AK027372; BAB55068.1; ALT_INIT; mRNA.
DR RefSeq; NP_116179.2; NM_032790.3. [Q96D31-1]
DR PDB; 2MAK; NMR; -; B/D=272-292.
DR PDB; 4EHQ; X-ray; 1.90 A; G=69-88.
DR PDBsum; 2MAK; -.
DR PDBsum; 4EHQ; -.
DR AlphaFoldDB; Q96D31; -.
DR BMRB; Q96D31; -.
DR SMR; Q96D31; -.
DR BioGRID; 124321; 103.
DR CORUM; Q96D31; -.
DR DIP; DIP-46289N; -.
DR IntAct; Q96D31; 16.
DR MINT; Q96D31; -.
DR STRING; 9606.ENSP00000480616; -.
DR BindingDB; Q96D31; -.
DR ChEMBL; CHEMBL2384891; -.
DR GuidetoPHARMACOLOGY; 2964; -.
DR TCDB; 1.A.52.1.1; the ca(2+) release-activated ca(2+) (crac) channel (crac-c) family.
DR GlyGen; Q96D31; 1 site.
DR iPTMnet; Q96D31; -.
DR PhosphoSitePlus; Q96D31; -.
DR SwissPalm; Q96D31; -.
DR BioMuta; ORAI1; -.
DR DMDM; 97180269; -.
DR EPD; Q96D31; -.
DR jPOST; Q96D31; -.
DR MassIVE; Q96D31; -.
DR MaxQB; Q96D31; -.
DR PaxDb; Q96D31; -.
DR PeptideAtlas; Q96D31; -.
DR PRIDE; Q96D31; -.
DR ProteomicsDB; 76249; -. [Q96D31-1]
DR TopDownProteomics; Q96D31-2; -. [Q96D31-2]
DR ABCD; Q96D31; 12 sequenced antibodies.
DR Antibodypedia; 73527; 485 antibodies from 38 providers.
DR DNASU; 84876; -.
DR Ensembl; ENST00000617316.2; ENSP00000482568.2; ENSG00000276045.3. [Q96D31-1]
DR GeneID; 84876; -.
DR KEGG; hsa:84876; -.
DR UCSC; uc031zps.1; human. [Q96D31-1]
DR CTD; 84876; -.
DR DisGeNET; 84876; -.
DR GeneCards; ORAI1; -.
DR HGNC; HGNC:25896; ORAI1.
DR HPA; ENSG00000276045; Tissue enhanced (skeletal).
DR MalaCards; ORAI1; -.
DR MIM; 610277; gene.
DR MIM; 612782; phenotype.
DR MIM; 615883; phenotype.
DR neXtProt; NX_Q96D31; -.
DR OpenTargets; ENSG00000276045; -.
DR Orphanet; 317428; Combined immunodeficiency due to ORAI1 deficiency.
DR Orphanet; 3204; Stormorken-Sjaastad-Langslet syndrome.
DR Orphanet; 2593; Tubular aggregate myopathy.
DR PharmGKB; PA162398445; -.
DR VEuPathDB; HostDB:ENSG00000276045; -.
DR eggNOG; KOG4298; Eukaryota.
DR GeneTree; ENSGT00390000015354; -.
DR InParanoid; Q96D31; -.
DR OMA; ADHDYPR; -.
DR PhylomeDB; Q96D31; -.
DR TreeFam; TF313576; -.
DR PathwayCommons; Q96D31; -.
DR Reactome; R-HSA-139853; Elevation of cytosolic Ca2+ levels.
DR Reactome; R-HSA-5578775; Ion homeostasis.
DR Reactome; R-HSA-983695; Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
DR SignaLink; Q96D31; -.
DR SIGNOR; Q96D31; -.
DR BioGRID-ORCS; 84876; 11 hits in 1069 CRISPR screens.
DR ChiTaRS; ORAI1; human.
DR GeneWiki; ORAI1; -.
DR GenomeRNAi; 84876; -.
DR Pharos; Q96D31; Tchem.
DR PRO; PR:Q96D31; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q96D31; protein.
DR Bgee; ENSG00000276045; Expressed in granulocyte and 109 other tissues.
DR ExpressionAtlas; Q96D31; baseline and differential.
DR Genevisible; Q96D31; HS.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0034704; C:calcium channel complex; ISS:FlyBase.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0044853; C:plasma membrane raft; IDA:UniProtKB.
DR GO; GO:0005262; F:calcium channel activity; IDA:FlyBase.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0015279; F:store-operated calcium channel activity; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0070509; P:calcium ion import; IEA:Ensembl.
DR GO; GO:0070588; P:calcium ion transmembrane transport; IDA:FlyBase.
DR GO; GO:0061180; P:mammary gland epithelium development; IEA:Ensembl.
DR GO; GO:0045762; P:positive regulation of adenylate cyclase activity; IDA:UniProtKB.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; IDA:UniProtKB.
DR GO; GO:0051924; P:regulation of calcium ion transport; IMP:UniProtKB.
DR GO; GO:0002115; P:store-operated calcium entry; IDA:UniProtKB.
DR Gene3D; 1.20.140.140; -; 1.
DR InterPro; IPR012446; CRAC_channel.
DR InterPro; IPR038350; Orai_sf.
DR PANTHER; PTHR31501; PTHR31501; 1.
DR Pfam; PF07856; Orai-1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; Alternative initiation; Calcium;
KW Calcium channel; Calcium transport; Calmodulin-binding; Cell membrane;
KW Disease variant; Glycoprotein; Immunity; Ion channel; Ion transport;
KW Membrane; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport; Ubl conjugation.
FT CHAIN 1..301
FT /note="Calcium release-activated calcium channel protein 1"
FT /id="PRO_0000234381"
FT TOPO_DOM 1..87
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:19249086"
FT TRANSMEM 88..105
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 106..119
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 120..140
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 141..173
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 174..194
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 195..234
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 235..255
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 256..301
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:19249086"
FT REGION 1..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 70..90
FT /note="Interaction with STIM1"
FT REGION 205..225
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 272..292
FT /note="Interaction with STIM1"
FT COMPBIAS 1..15
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 295
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 298
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT CARBOHYD 223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26956484"
FT VAR_SEQ 1..70
FT /note="Missing (in isoform beta)"
FT /evidence="ECO:0000305"
FT /id="VSP_044421"
FT VARIANT 91
FT /note="R -> W (in IMD9; dbSNP:rs118203993)"
FT /evidence="ECO:0000269|PubMed:16582901"
FT /id="VAR_026226"
FT VARIANT 98
FT /note="G -> S (in TAM2; constitutively active Ca(+2)
FT channel, independently of STIM proteins; no effect on
FT localization to the cell membrane; dbSNP:rs786204796)"
FT /evidence="ECO:0000269|PubMed:28058752"
FT /id="VAR_078083"
FT VARIANT 107
FT /note="V -> M (in TAM2; constitutively active Ca(+2)
FT channel, independently of STIM proteins; no effect on
FT localization to the cell membrane)"
FT /evidence="ECO:0000269|PubMed:28058752"
FT /id="VAR_078084"
FT VARIANT 184
FT /note="T -> M (in TAM2; mediates excessive Ca(2+) entry
FT when gated by STIM1; no effect on localization to the cell
FT membrane; dbSNP:rs1555324111)"
FT /evidence="ECO:0000269|PubMed:28058752"
FT /id="VAR_078085"
FT VARIANT 218
FT /note="S -> G (in dbSNP:rs3741596)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_038608"
FT VARIANT 245
FT /note="P -> L (in TAM2; increases activation of the Ca2+
FT release-activated Ca2+ (CRAC) channel; dbSNP:rs587777528)"
FT /evidence="ECO:0000269|PubMed:24591628"
FT /id="VAR_071473"
FT MUTAGEN 85..87
FT /note="KLK->ALA: Impairs interaction with CRACR2A/EFCAB4B."
FT /evidence="ECO:0000269|PubMed:20418871"
FT MUTAGEN 195
FT /note="C->S: Abolishes oxidation and channel inhibition."
FT /evidence="ECO:0000269|PubMed:20354224,
FT ECO:0000269|PubMed:28219928"
FT MUTAGEN 223
FT /note="N->A: Increases channel activity in T cells but does
FT not affect cell surface location."
FT /evidence="ECO:0000269|PubMed:26956484"
FT MUTAGEN 273
FT /note="L->S: Strongly reduces the interaction with ATP2C1."
FT /evidence="ECO:0000269|PubMed:20887894"
FT MUTAGEN 281
FT /note="R->A: Strongly reduces calcium current."
FT /evidence="ECO:0000269|PubMed:24351972"
FT MUTAGEN 284
FT /note="D->A: Reduces the maximum current; when associated
FT with A-287 and A-291."
FT /evidence="ECO:0000269|PubMed:24351972"
FT MUTAGEN 286
FT /note="L->S: Strongly reduces calcium current."
FT /evidence="ECO:0000269|PubMed:24351972"
FT MUTAGEN 287
FT /note="D->A: Reduces the maximum current; when associated
FT with A-284 and A-291."
FT /evidence="ECO:0000269|PubMed:24351972"
FT MUTAGEN 289
FT /note="R->A: Strongly reduces calcium current."
FT /evidence="ECO:0000269|PubMed:24351972"
FT MUTAGEN 291
FT /note="D->A: Reduces the maximum current; when associated
FT with A-284 and A-287."
FT /evidence="ECO:0000269|PubMed:24351972"
FT CONFLICT 255
FT /note="V -> F (in Ref. 2; BAB55068)"
FT /evidence="ECO:0000305"
FT HELIX 76..86
FT /evidence="ECO:0007829|PDB:4EHQ"
FT HELIX 272..288
FT /evidence="ECO:0007829|PDB:2MAK"
SQ SEQUENCE 301 AA; 32668 MW; F85F7C06F36628D4 CRC64;
MHPEPAPPPS RSSPELPPSG GSTTSGSRRS RRRSGDGEPP GAPPPPPSAV TYPDWIGQSY
SEVMSLNEHS MQALSWRKLY LSRAKLKASS RTSALLSGFA MVAMVEVQLD ADHDYPPGLL
IAFSACTTVL VAVHLFALMI STCILPNIEA VSNVHNLNSV KESPHERMHR HIELAWAFST
VIGTLLFLAE VVLLCWVKFL PLKKQPGQPR PTSKPPASGA AANVSTSGIT PGQAAAIAST
TIMVPFGLIF IVFAVHFYRS LVSHKTDRQF QELNELAEFA RLQDQLDHRG DHPLTPGSHY
A
