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The CRAC channel protein, Orai1 (CRACM1) (Prakriya et al. 2006), complexed with the STIM1 or STIM2 protein (Feske et al., 2006). Replacement of the conserved glutamate in the first TMS  with glutamine (E106Q) acts as a dominant-negative protein, and substitution with aspartate (E106D) enhances Na+, Ba2+, and Sr2+ permeation relative to Ca2+. Mutating E190Q in TMS3 also affects channel selectivity, suggesting that glutamate residues in both TMS1 and TMS3 face the lumen of the pore (Vig et al. 2006). The Orai1:Stim stoichiometry = 4:2 (Ji et al., 2008). Human Orai1 and Orai3 channels are dimeric in the closed resting state and open states. They are tetrameric when complexed with STIM1 (Demuro et al., 2011). A dimeric form catalyzes nonselective cation conductance in the STIM1-independent mode.  STIM1 domains have been characterized (How et al. 2013). Alternative translation initiation of the Orai1 message produces long and short types of Ca2+ channels with distinct signaling and regulatory properties (Desai et al. 2015).  STIM2 plays roles similar to STIM1 in regulating basal cytosolic and endoplasmic reticulum Ca2+ concentrations by controling Orai1, 2 and 3.  STIM2 may inhibit STIM1-mediated Ca2+ influx.  It also regulates protein kinase A-dependent phosphorylation and trafficking of AMPA receptors (TC# 1.A.10) (Garcia-Alvarez et al. 2015). A mechanistic model for ROS (H2O2)-mediated inhibition of Orai1 has been determined (Alansary et al. 2016). Regions that are important for the optimal assembly of hetero-oligomers composed of full-length STIM1 with its minimal STIM1-ORAI activating region, SOAR, have been identified (Ma et al. 2017). Orai1 may be multifunctional (Carrell et al. 2016). Activatioin of Orai1 requires communication between the N-terminus and loop 2 (Fahrner et al. 2017). STIM1 dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions (Zhou et al. 2018). SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function. In addition to being an ER Ca2+ sensor, STIM1 functions within the PM to exert control over the operation of SOCs. As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca2+-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis (Spassova et al. 2006). STIM1 also contributes to smooth muscle contractility (Feldman et al. 2017). STIM1-mediated Orai1 channel gating, involves bridges between TMS 1 and the surrounding TMSs 2/3 ring, and these are critical for conveying the gating signal to the pore (Yeung et al. 2018). A review article summarizes the current high resolution structural data on specific EF-hand, sterile alpha motif and coiled-coil interactions which drive STIM function in the activation of Orai1 channels (Novello et al. 2018). Orai1 and STIM1 are involved in tubular aggregate myopathy (Wu et al. 2018). Knowledge of the structure-function relationships of CRAC channels, with a focus on key structural elements that mediate the STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1 has been discussed (Nguyen et al. 2018). While STIM1 is the native channel opener, a chemical modulator is 2-aminoethoxydiphenyl borate (2-APB) (Ali et al. 2017). ORAI1 channel gating and selectivity iare differentially altered by natural mutations in the first and third transmembrane domains (Bulla et al. 2018). Stim1 responds to both ER Ca2+ depletion and heat, mediates temperature-induced Ca2+ influx in skin keratinocytes via coupling to Orai Ca2+ channels in the plasma membrane, and thereby brings about thermosensing (Liu et al. 2019). Possibly, the interplay between STIM1 alpha3 and Orai1 TM3 allows STIM1 coupling to be transmitted into physiological CRAC channel activation (Butorac et al. 2019). Blockage of store-operated Ca2+ influx by synta66 is mediated by direct inhibition of the Ca2+ selective orai1 pore (Waldherr et al. 2020). The carboxy terminal coiled-coil region modulates Orai1 internalization during meiosis (Hodeify et al. 2021). ORAI1 mutations disrupt channel trafficking, resulting in combined immunodeficiency (Yu et al. 2021). Orai channel C-terminal peptides are key modulators of STIM-Orai coupling and calcium signal generation (Baraniak et al. 2021).

Accession Number:Q96D31
Protein Name:Orai-1
Molecular Weight:32668.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate Sr2+, Ba2+, monovalent cations, Ca2+

Cross database links:

DIP: DIP-46289N
RefSeq: NP_116179.2   
Entrez Gene ID: 84876   
Pfam: PF07856   
OMIM: 610277  gene
612782  phenotype
KEGG: hsa:84876   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0005515 F:protein binding
GO:0015279 F:store-operated calcium channel activity
GO:0006816 P:calcium ion transport
GO:0006955 P:immune response
GO:0051928 P:positive regulation of calcium ion transport

References (10)

[1] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota   14702039
[3] “A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients.”  Feske   16147976
[4] “Orai1 and STIM reconstitute store-operated calcium channel function.”  Soboloff   16766533
[5] “Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1.”  Mercer   16807233
[6] “Amplification of CRAC current by STIM1 and CRACM1 (Orai1).”  Peinelt   16733527
[7] “CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry.”  Vig   16645049
[8] “STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation.”  Parvez   17905723
[9] “A quantitative atlas of mitotic phosphorylation.”  Dephoure   18669648
[10] “A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.”  Feske   16582901
2MAK   4EHQ     

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FASTA formatted sequence
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