ORAI1

Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene.^[5][6][7] Orai channels play an important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency (SCID) in humans^[5] The mammalian orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other ion channel family of any other known proteins. They have 4 transmembrane domains and form hexamers.

ORAI1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2MAK, 4EHQ
Identifiers
Aliases	ORAI1, CRACM1, IMD9, ORAT1, TAM2, TMEM142A, ORAI calcium release-activated calcium modulator 1
External IDs	OMIM: 610277; MGI: 1925542; HomoloGene: 13117; GeneCards: ORAI1; OMA:ORAI1 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q24.31 Start 121,626,550 bp[1] End 121,642,677 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 F Start 123,153,137 bp[2] End 123,168,519 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte muscle of thigh skin of leg skin of abdomen gastrocnemius muscle monocyte blood spleen olfactory zone of nasal mucosa gonad Top expressed in granulocyte triceps brachii muscle temporal muscle sternocleidomastoid muscle tibiofemoral joint extraocular muscle zygote digastric muscle muscle of thigh primary oocyte More reference expression data BioGPS n/a
Gene ontology Molecular function store-operated calcium channel activity calcium channel activity calmodulin binding protein binding identical protein binding Cellular component integral component of membrane membrane integral component of plasma membrane plasma membrane Biological process regulation of calcium ion transport adaptive immune response immune system process ion transport calcium ion transmembrane transport calcium ion transport positive regulation of calcium ion transport store-operated calcium entry transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84876 109305 Ensembl ENSG00000276045 ENSMUSG00000049686 UniProt Q96D31 Q8BWG9 RefSeq (mRNA) NM_032790 NM_175423 RefSeq (protein) NP_116179 NP_780632 Location (UCSC) Chr 12: 121.63 – 121.64 Mb Chr 5: 123.15 – 123.17 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure and function

ORAI channels are activated upon the depletion of internal calcium stores, which is called the "store-operated" or the "capacitative" mechanism.^[8] They are molecular constituents of the "calcium release activated calcium currents" (ICRAC). Upon activation of phospholipase C by various cell surface receptors, inositol trisphosphate is formed that releases calcium from the endoplasmic reticulum. The decreased calcium concentration in the endoplasmic reticulum is sensed by the STIM1 protein. STIM1 clusters upon the depletion of the calcium stores and forms "puncta", and relocates near the plasma membrane, where it activates ORAI1 via protein-protein interaction.^{[9][10][11][12]}

In 2012, a 3.35-angstrom (Å) crystal structure of the Drosophila Orai channel, which shares 73% sequence identity with human Orai1 within its transmembrane region, was published.^[13] The structure, thought to show the closed state of the channel, revealed that a single channel is composed of six Orai subunits, with the transmembrane domains arranged in concentric rings around a central aqueous pore formed exclusively by the first transmembrane helix of each subunit. Transmembrane helices 2 and 3 surround TM1 and are hypothesized to shield it from the surrounding lipid bilayer and provide structural support. The fourth transmembrane helix forms the outermost layer.

Clinical relevance

ORAI1 mutations are associated with Immunodeficiency 9 and Tubular aggregate myopathy type 2 (TAM2).^[14]

Ligands

Inhibitors

• CM-4620

References

1. GRCh38: Ensembl release 89: ENSG00000276045 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000049686 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (May 2006). "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function". Nature. 441 (7090): 179–85. Bibcode:2006Natur.441..179F. doi:10.1038/nature04702. PMID 16582901. S2CID 1605392.
6. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (May 2006). "CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry". Science. 312 (5777): 1220–3. Bibcode:2006Sci...312.1220V. doi:10.1126/science.1127883. PMC 5685805. PMID 16645049.
7. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (June 2006). "Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activated Ca(2+) channel activity". Proceedings of the National Academy of Sciences of the United States of America. 103 (24): 9357–62. doi:10.1073/pnas.0603161103. PMC 1482614. PMID 16751269.
8. Putney JW (September 2009). "Capacitative calcium entry: from concept to molecules". Immunological Reviews. 231 (1): 10–22. doi:10.1111/j.1600-065X.2009.00810.x. PMID 19754887. S2CID 32303982.
9. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (March 2009). "STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1". Cell. 136 (5): 876–90. doi:10.1016/j.cell.2009.02.014. PMC 2670439. PMID 19249086.
10. Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG (January 2010). "STIM1 gates the store-operated calcium channel ORAI1 in vitro". Nature Structural & Molecular Biology. 17 (1): 112–6. doi:10.1038/nsmb.1724. PMC 2902271. PMID 20037597.
11. Gudlur A, Zhou Y, Hogan PG (2013-01-01). "STIM-ORAI interactions that control the CRAC channel". Current Topics in Membranes. 71: 33–58. doi:10.1016/b978-0-12-407870-3.00002-0. ISBN 9780124078703. PMID 23890110.
12. Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, Stathopulos PB, Ikura M, Rao A, Hogan PG (August 2013). "Initial activation of STIM1, the regulator of store-operated calcium entry". Nature Structural & Molecular Biology. 20 (8): 973–81. doi:10.1038/nsmb.2625. PMC 3784406. PMID 23851458.
13. Hou X, Pedi L, Diver MM, Long SB (December 2012). "Crystal structure of the calcium release-activated calcium channel Orai". Science. 338 (6112): 1308–13. Bibcode:2012Sci...338.1308H. doi:10.1126/science.1228757. PMC 3695727. PMID 23180775.
14. "ORAI CALCIUM RELEASE-ACTIVATED CALCIUM MODULATOR 1; ORAI1". www.omim.org. Retrieved 2023-11-13.