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Protein

Calcium release-activated calcium channel protein 1

Gene

ORAI1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 (PubMed:16582901, PubMed:16645049, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:19249086, PubMed:23307288, PubMed:24351972, PubMed:24591628, PubMed:28219928). 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 (PubMed:16582901).10 Publications

Miscellaneous

According to a report, ORAI1 has been shown to colocalize with UBQLN1 in the autophagosome as a target for autophagic degradation; ORAI1 is however not an autophagosomal protein.1 Publication
In Greek mythology, the 'Orai' are the keepers of the gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene (peace).1 Publication

GO - Molecular functioni

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • positive regulation of calcium ion transport Source: UniProtKB
  • regulation of calcium ion transport Source: UniProtKB
  • store-operated calcium entry Source: UniProtKB

Keywordsi

Molecular functionCalcium channel, Calmodulin-binding, Ion channel
Biological processAdaptive immunity, Calcium transport, Immunity, Ion transport, Transport
LigandCalcium

Enzyme and pathway databases

ReactomeiR-HSA-139853. Elevation of cytosolic Ca2+ levels.
R-HSA-5578775. Ion homeostasis.
R-HSA-983695. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
SIGNORiQ96D31.

Protein family/group databases

TCDBi1.A.52.1.1. the ca(2+) release-activated ca(2+) (crac) channel (crac-c) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium release-activated calcium channel protein 1
Alternative name(s):
Protein orai-1
Transmembrane protein 142A
Gene namesi
Name:ORAI1
Synonyms:CRACM1, TMEM142A
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Unplaced

Organism-specific databases

EuPathDBiHostDB:ENSG00000276045.1.
HGNCiHGNC:25896. ORAI1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 87Cytoplasmic1 PublicationAdd BLAST87
Transmembranei88 – 105HelicalSequence analysisAdd BLAST18
Topological domaini106 – 119ExtracellularSequence analysisAdd BLAST14
Transmembranei120 – 140HelicalSequence analysisAdd BLAST21
Topological domaini141 – 173CytoplasmicSequence analysisAdd BLAST33
Transmembranei174 – 194HelicalSequence analysisAdd BLAST21
Topological domaini195 – 234ExtracellularSequence analysisAdd BLAST40
Transmembranei235 – 255HelicalSequence analysisAdd BLAST21
Topological domaini256 – 301Cytoplasmic1 PublicationAdd BLAST46

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Immunodeficiency 9 (IMD9)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, and normal lymphocytes counts and serum immunoglobulin levels. In surviving patients ectodermal dysplasia with anhidrosis and non-progressive myopathy may be observed.
See also OMIM:612782
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02622691R → W in IMD9. 1 PublicationCorresponds to variant dbSNP:rs118203993Ensembl.1
Myopathy, tubular aggregate, 2 (TAM2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. TAM2 patients have myopathy and pupillary abnormalities.
See also OMIM:615883
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07808398G → S in TAM2; constitutively active Ca(+2) channel, independently of STIM proteins; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_078084107V → M in TAM2; constitutively active Ca(+2) channel, independently of STIM proteins; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_078085184T → M in TAM2; mediates excessive Ca(2+) entry when gated by STIM1; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_071473245P → L in TAM2; increases activation of the Ca2+ release-activated Ca2+ (CRAC) channel. 1 PublicationCorresponds to variant dbSNP:rs587777528Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi85 – 87KLK → ALA: Impairs interaction with CRACR2A/EFCAB4B. 1 Publication3
Mutagenesisi195C → S: Abolishes oxidation and channel inhibition. 1 Publication1
Mutagenesisi281R → A: Strongly reduces calcium current. 1 Publication1
Mutagenesisi284D → A: Reduces the maximum current; when associated with A-287 and A-291. 1 Publication1
Mutagenesisi286L → S: Strongly reduces calcium current. 1 Publication1
Mutagenesisi287D → A: Reduces the maximum current; when associated with A-284 and A-291. 1 Publication1
Mutagenesisi289R → A: Strongly reduces calcium current. 1 Publication1
Mutagenesisi291D → A: Reduces the maximum current; when associated with A-284 and A-287. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi84876.
MalaCardsiORAI1.
MIMi612782. phenotype.
615883. phenotype.
Orphaneti317428. Combined immunodeficiency due to ORAI1 deficiency.
2593. Tubular aggregate myopathy.
PharmGKBiPA162398445.

Chemistry databases

ChEMBLiCHEMBL2384891.

Polymorphism and mutation databases

DMDMi97180269.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002343811 – 301Calcium release-activated calcium channel protein 1Add BLAST301

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi223N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei295PhosphothreonineCombined sources1
Modified residuei298PhosphoserineCombined sources1

Post-translational modificationi

N-glycosylated.1 Publication
Ubiquitinated.1 Publication
Cys-195 is oxidated, leading to inactivate channel activity.1 Publication

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ96D31.
MaxQBiQ96D31.
PaxDbiQ96D31.
PeptideAtlasiQ96D31.
PRIDEiQ96D31.
TopDownProteomicsiQ96D31-2. [Q96D31-2]

PTM databases

iPTMnetiQ96D31.
PhosphoSitePlusiQ96D31.
SwissPalmiQ96D31.

Expressioni

Gene expression databases

BgeeiENSG00000276045.
CleanExiHS_ORAI1.
GenevisibleiQ96D31. HS.

Organism-specific databases

HPAiHPA016583.
HPA061823.

Interactioni

Subunit structurei

Interacts with STIM1 and STIM2; this regulates channel activity (PubMed:17905723, PubMed:19249086, PubMed:24351972, PubMed:28219928). Interacts with CALM; this may displace STIM1 and STIM2 and might thereby modulate channel activity (PubMed:23109337). Interacts with CRACR2A/EFCAB4B; the interaction is direct and takes place in absence of Ca2+ (PubMed:20418871). Forms a complex with CRACR2A/EFCAB4B and STIM1 at low concentration of Ca2+, the complex dissociates at elevated Ca2+ concentrations. Interacts with ASPH (isoform 8) (PubMed:22586105). Interacts with SLC35G1 (PubMed:22084111). Interacts with UBQLN1 (PubMed:23307288).9 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • calmodulin binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct

Protein-protein interaction databases

BioGridi124321. 34 interactors.
CORUMiQ96D31.
DIPiDIP-46289N.
IntActiQ96D31. 10 interactors.
MINTiMINT-6780078.
STRINGi9606.ENSP00000328216.

Chemistry databases

BindingDBiQ96D31.

Structurei

Secondary structure

1301
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi76 – 86Combined sources11
Helixi272 – 288Combined sources17

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MAKNMR-B/D272-292[»]
4EHQX-ray1.90G69-88[»]
ProteinModelPortaliQ96D31.
SMRiQ96D31.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni70 – 90Interaction with STIM1Add BLAST21
Regioni272 – 292Interaction with STIM1Add BLAST21

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi3 – 47Pro-richAdd BLAST45

Sequence similaritiesi

Belongs to the Orai family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4298. Eukaryota.
ENOG4110DSB. LUCA.
HOGENOMiHOG000246925.
HOVERGENiHBG081343.
InParanoidiQ96D31.
KOiK16056.
OrthoDBiEOG091G0E4P.
PhylomeDBiQ96D31.
TreeFamiTF313576.

Family and domain databases

InterProiView protein in InterPro
IPR012446. CRAC_channel.
PANTHERiPTHR31501. PTHR31501. 1 hit.
PfamiView protein in Pfam
PF07856. Orai-1. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform alpha (identifier: Q96D31-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MHPEPAPPPS RSSPELPPSG GSTTSGSRRS RRRSGDGEPP GAPPPPPSAV
60 70 80 90 100
TYPDWIGQSY SEVMSLNEHS MQALSWRKLY LSRAKLKASS RTSALLSGFA
110 120 130 140 150
MVAMVEVQLD ADHDYPPGLL IAFSACTTVL VAVHLFALMI STCILPNIEA
160 170 180 190 200
VSNVHNLNSV KESPHERMHR HIELAWAFST VIGTLLFLAE VVLLCWVKFL
210 220 230 240 250
PLKKQPGQPR PTSKPPASGA AANVSTSGIT PGQAAAIAST TIMVPFGLIF
260 270 280 290 300
IVFAVHFYRS LVSHKTDRQF QELNELAEFA RLQDQLDHRG DHPLTPGSHY

A
Length:301
Mass (Da):32,668
Last modified:May 16, 2006 - v2
Checksum:iF85F7C06F36628D4
GO
Isoform beta (identifier: Q96D31-2) [UniParc]FASTAAdd to basket

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

Show »
Length:231
Mass (Da):25,337
Checksum:i0F7EEBB6DADB9005
GO

Sequence cautioni

Q96D31: The sequence AAH13386 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
Q96D31: The sequence AAI04634 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
Q96D31: The sequence BAB55068 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti255V → F in BAB55068 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02622691R → W in IMD9. 1 PublicationCorresponds to variant dbSNP:rs118203993Ensembl.1
Natural variantiVAR_07808398G → S in TAM2; constitutively active Ca(+2) channel, independently of STIM proteins; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_078084107V → M in TAM2; constitutively active Ca(+2) channel, independently of STIM proteins; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_078085184T → M in TAM2; mediates excessive Ca(2+) entry when gated by STIM1; no effect on localization to the cell membrane. 1 Publication1
Natural variantiVAR_038608218S → G2 PublicationsCorresponds to variant dbSNP:rs3741596Ensembl.1
Natural variantiVAR_071473245P → L in TAM2; increases activation of the Ca2+ release-activated Ca2+ (CRAC) channel. 1 PublicationCorresponds to variant dbSNP:rs587777528Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0444211 – 70Missing in isoform beta. CuratedAdd BLAST70

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
RefSeqiNP_116179.2. NM_032790.3. [Q96D31-1]
UniGeneiHs.55148.

Genome annotation databases

EnsembliENST00000616379; ENSP00000480616; ENSG00000276045.
GeneIDi84876.
KEGGihsa:84876.
UCSCiuc031zps.1. human. [Q96D31-1]

Keywords - Coding sequence diversityi

Alternative initiation

Similar proteinsi

Entry informationi

Entry nameiCRCM1_HUMAN
AccessioniPrimary (citable) accession number: Q96D31
Secondary accession number(s): Q3MHV3
, Q6DHX2, Q96BP7, Q96K71
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 16, 2006
Last sequence update: May 16, 2006
Last modified: October 25, 2017
This is version 130 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families