ORAI1

ORAI1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases ORAI1, CRACM1, IMD9, ORAT1, TAM2, TMEM142A, ORAI calcium release-activated calcium modulator 1
External IDs MGI: 1925542 HomoloGene: 13117 GeneCards: ORAI1
Orthologs
Species Human Mouse
Entrez

84876

109305

Ensembl

ENSG00000276045

ENSMUSG00000049686

UniProt

Q96D31

Q8BWG9

RefSeq (mRNA)

NM_032790

NM_175423

RefSeq (protein)

NP_116179.2

NP_780632.1

Location (UCSC) Chr 12: 121.63 – 121.64 Mb Chr 5: 123.02 – 123.03 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene.[3][4][5] 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[3] 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.

Structure and function

Orai channels are activated upon the depletion of internal calcium stores, which is called the "store-operated" or the "capacitative" mechanism.[6] 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.[7][8][9][10]

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.[11] 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. The N- and C-termini, which contain the binding sites for STIM1, were found to be extensions of the first and fourth transmembrane helices.

References

  1. "Human PubMed Reference:".
  2. "Mouse PubMed Reference:".
  3. 1 2 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. doi:10.1038/nature04702. PMID 16582901.
  4. 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. doi:10.1126/science.1127883. PMID 16645049.
  5. 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. PMID 16751269.
  6. 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.
  7. 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 2670439Freely accessible. PMID 19249086.
  8. 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 2902271Freely accessible. PMID 20037597.
  9. 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. PMID 23890110.
  10. 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 3784406Freely accessible. PMID 23851458.
  11. 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. doi:10.1126/science.1228757. PMC 3695727Freely accessible. PMID 23180775.
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