Q96D31 (CRCM1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Calcium release-activated calcium channel protein 1

Alternative name(s):
Protein orai-1
Transmembrane protein 142A

Gene names

Name:	ORAI1
Synonyms:	CRACM1, TMEM142A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	301 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Ca2+ release-activated Ca2+ (CRAC) channel subunit which mediates Ca2+ influx following depletion of intracellular Ca2+ stores and channel activation by the Ca2+ sensor, STIM1. CRAC channels are the main pathway for Ca2+ influx in T-cells and promote the immune response to pathogens by activating the transcription factor NFAT. Ref.4 Ref.5 Ref.6 Ref.7 Ref.13
Subunit structure	Interacts with STIM1 and STIM2. Interacts with EFCAB4B/CRACR2A; the interaction is direct and takes place in absence of Ca2+. Forms a complex with EFCAB4B/CRACR2A and STIM1 at low concentration of Ca2+, the complex dissociates at elevated Ca2+ concentrations. Interacts with ASPH (isoform 8). Ref.8 Ref.11 Ref.12
Subcellular location	Cell membrane; Multi-pass membrane protein. Note: Isoform beta is more mobile in the plasma membrane. Ref.7 Ref.10 Ref.13
Involvement in disease	Immune dysfunction with T-cell inactivation due to calcium entry defect 1 (IDTICED1) [MIM:612782]: An immune disorder characterized by recurrent infections, impaired T-cell activation and proliferative response, decreased T-cell production of cytokines, and normal lymphocytes counts and serum immunoglobulin levels. In surviving patients ectodermal dysplasia with anhydrosis and non-progressive myopathy may be observed. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3 Ref.13
Miscellaneous	In Greek mythology, the 'Orai' are the keepers of the gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene (peace).
Sequence similarities	Belongs to the Orai family.
Sequence caution	The sequence AAH13386.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAI04634.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAB55068.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Adaptive immunity Calcium transport Immunity Ion transport Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative initiation
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
Ligand	Calcium
Molecular function	Calcium channel Ion channel
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Traceable author statement. Source: Reactome positive regulation of calcium ion transport Inferred from direct assay Ref.7Ref.6Ref.4Ref.5. Source: UniProtKB store-operated calcium entry Inferred from electronic annotation. Source: Compara
Cellular_component	integral to plasma membrane Inferred from direct assay Ref.7. Source: UniProtKB protein complex Inferred from electronic annotation. Source: Compara
Molecular_function	store-operated calcium channel activity Inferred from direct assay Ref.7Ref.6Ref.4Ref.5. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATP2C2	O75185	10	EBI-2291476,EBI-2939806
EFCAB4B	Q9BSW2	6	EBI-2291476,EBI-739773
STIM1	Q13586	11	EBI-2291476,EBI-448878

Alternative products

This entry describes 2 isoforms produced by alternative initiation. [Align] [Select]

Isoform alpha (identifier: Q96D31-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform beta (identifier: Q96D31-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-70: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 301

301

Calcium release-activated calcium channel protein 1

PRO_0000234381

Regions

Topological domain

1 – 87

87

Cytoplasmic Potential

Transmembrane

88 – 105

18

Helical; Potential

Topological domain

106 – 119

14

Extracellular Potential

Transmembrane

120 – 140

21

Helical; Potential

Topological domain

141 – 173

33

Cytoplasmic Potential

Transmembrane

174 – 194

21

Helical; Potential

Topological domain

195 – 234

40

Extracellular Potential

Transmembrane

235 – 255

21

Helical; Potential

Topological domain

256 – 301

46

Cytoplasmic Potential

Compositional bias

3 – 47

45

Pro-rich

Amino acid modifications

Modified residue

295

1

Phosphothreonine Ref.9

Modified residue

298

1

Phosphoserine Ref.9

Glycosylation

223

1

N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence

1 – 70

70

Missing in isoform beta.

VSP_044421

Natural variant

91

1

R → W in IDTICED1. Ref.13

VAR_026226

Natural variant

218

1

S → G. Ref.1 Ref.2
Corresponds to variant rs3741596 [ dbSNP | Ensembl ].

VAR_038608

Experimental info

Mutagenesis

85 – 87

3

KLK → ALA: Impairs interaction with EFCAB4B/CRACR2A. Ref.12

Sequence conflict

255

1

V → F in BAB55068. Ref.2

Secondary structure

1

.

.

.

301

Helix Strand Turn

Details...

Helix

76 – 86

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform alpha [UniParc]. Last modified May 16, 2006. Version 2. Checksum: F85F7C06F36628D4	FASTA	301	32,668
	10 20 30 40 50 60 MHPEPAPPPS RSSPELPPSG GSTTSGSRRS RRRSGDGEPP GAPPPPPSAV TYPDWIGQSY 70 80 90 100 110 120 SEVMSLNEHS MQALSWRKLY LSRAKLKASS RTSALLSGFA MVAMVEVQLD ADHDYPPGLL 130 140 150 160 170 180 IAFSACTTVL VAVHLFALMI STCILPNIEA VSNVHNLNSV KESPHERMHR HIELAWAFST 190 200 210 220 230 240 VIGTLLFLAE VVLLCWVKFL PLKKQPGQPR PTSKPPASGA AANVSTSGIT PGQAAAIAST 250 260 270 280 290 300 TIMVPFGLIF IVFAVHFYRS LVSHKTDRQF QELNELAEFA RLQDQLDHRG DHPLTPGSHY A
	Isoform beta [UniParc]. Checksum: 0F7EEBB6DADB9005	FASTA	231	25,337
	10 20 30 40 50 60 MQALSWRKLY LSRAKLKASS RTSALLSGFA MVAMVEVQLD ADHDYPPGLL IAFSACTTVL 70 80 90 100 110 120 VAVHLFALMI STCILPNIEA VSNVHNLNSV KESPHERMHR HIELAWAFST VIGTLLFLAE 130 140 150 160 170 180 VVLLCWVKFL PLKKQPGQPR PTSKPPASGA AANVSTSGIT PGQAAAIAST TIMVPFGLIF 190 200 210 220 230 IVFAVHFYRS LVSHKTDRQF QELNELAEFA RLQDQLDHRG DHPLTPGSHY A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA), VARIANT GLY-218. Tissue: Bone marrow, Ovary, Prostate and Uterus.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-301 (ISOFORM ALPHA), VARIANT GLY-218. Tissue: Mammary gland.
[3]	"A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients." Feske S., Prakriya M., Rao A., Lewis R.S. J. Exp. Med. 202:651-662(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN IDTICED1.
[4]	"Orai1 and STIM reconstitute store-operated calcium channel function." Soboloff J., Spassova M.A., Tang X.D., Hewavitharana T., Xu W., Gill D.L. J. Biol. Chem. 281:20661-20665(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1." Mercer J.C., Dehaven W.I., Smyth J.T., Wedel B., Boyles R.R., Bird G.S., Putney J.W. Jr. J. Biol. Chem. 281:24979-24990(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Amplification of CRAC current by STIM1 and CRACM1 (Orai1)." Peinelt C., Vig M., Koomoa D.L., Beck A., Nadler M.J.S., Koblan-Huberson M., Lis A., Fleig A., Penner R., Kinet J.-P. Nat. Cell Biol. 8:771-773(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry." Vig M., Peinelt C., Beck A., Koomoa D.L., Rabah D., Koblan-Huberson M., Kraft S., Turner H., Fleig A., Penner R., Kinet J.-P. Science 312:1220-1223(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[8]	"STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation." Parvez S., Beck A., Peinelt C., Soboloff J., Lis A., Monteilh-Zoller M., Gill D.L., Fleig A., Penner R. FASEB J. 22:752-761(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH STIM1 AND STIM2.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-295 AND SER-298, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"Alternative translation initiation gives rise to two isoforms of orai1 with distinct plasma membrane mobilities." Fukushima M., Tomita T., Janoshazi A., Putney J.W. J. Cell Sci. 125:4354-4361(2012) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE INITIATION, SUBCELLULAR LOCATION.
[11]	"Junctate is a Ca2+-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1)." Srikanth S., Jew M., Kim K.D., Yee M.K., Abramson J., Gwack Y. Proc. Natl. Acad. Sci. U.S.A. 109:8682-8687(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ASPH.
[12]	"A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells." Srikanth S., Jung H.J., Kim K.D., Souda P., Whitelegge J., Gwack Y. Nat. Cell Biol. 12:436-446(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EFCAB4B, MUTAGENESIS OF 85-LYS--LYS-87.
[13]	"A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function." Feske S., Gwack Y., Prakriya M., Srikanth S., Puppel S.-H., Tanasa B., Hogan P.G., Lewis R.S., Daly M., Rao A. Nature 441:179-185(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT IDTICED1 TRP-91, SUBCELLULAR LOCATION, FUNCTION.
+	Additional computationally mapped references.

Web resources

ORAI1base

ORAI1 mutation db

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

BC013386 mRNA. Translation: AAH13386.1. Different initiation.
BC015369 mRNA. Translation: AAH15369.2.
BC075831 mRNA. Translation: AAH75831.1.
BC104633 mRNA. Translation: AAI04634.1. Different initiation.
AK027372 mRNA. Translation: BAB55068.1. Different initiation.

IPI

IPI00303699.

RefSeq

NP_116179.2. NM_032790.3.

UniGene

Hs.55148.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4EHQ	X-ray	1.90	G	69-88	[»]

ProteinModelPortal

Q96D31.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-46289N.

IntAct

Q96D31. 4 interactions.

STRING

9606.ENSP00000328216.

Protein family/group databases

TCDB

1.A.52.1.1. Ca2+ release-activated Ca2+ (CRAC) channel (CRAC-C) family.

PTM databases

PhosphoSite

Q96D31.

Polymorphism databases

DMDM

97180269.

Proteomic databases

PaxDb

Q96D31.

PRIDE

Q96D31.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000330079; ENSP00000328216; ENSG00000182500.

GeneID

84876.

KEGG

hsa:84876.

UCSC

uc021rff.1. human.

Organism-specific databases

CTD

84876.

GeneCards

GC12P122064.

HGNC

HGNC:25896. ORAI1.

HPA

HPA016583.

MIM

610277. gene.
612782. phenotype.

neXtProt

NX_Q96D31.

Orphanet

169090. Severe combined immunodeficiency due to CRAC channel dysfunction.

PharmGKB

PA162398445.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG263788.

HOGENOM

HOG000246925.

HOVERGEN

HBG081343.

InParanoid

Q96D31.

KO

K16056.

OrthoDB

EOG4WH8MR.

Enzyme and pathway databases

Pathway_Interaction_DB

tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.

Reactome

REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q96D31.

Bgee

Q96D31.

CleanEx

HS_ORAI1.

Genevestigator

Q96D31.

GermOnline

ENSG00000182500. Homo sapiens.

Family and domain databases

InterPro

IPR012446. CRAC_channel.
[Graphical view]

Pfam

PF07856. Orai-1. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q96D31.

GenomeRNAi

84876.

NextBio

75181.

SOURCE

Search...

Entry information

Entry name

CRCM1_HUMAN

Accession

Primary (citable) accession number: Q96D31
Secondary accession number(s): Q3MHV3 , Q6DHX2, Q96BP7, Q96K71

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 16, 2006
Last sequence update:	May 16, 2006
Last modified:	May 1, 2013
This is version 84 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.