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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). Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation (Grieve et al. 2021). STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells (Krishnan et al. 2022). Gating checkpoints in the Orai1 calcium channel have been identified (Augustynek et al. 2022).  Photocrosslinking-induced CRAC channel-like Orai1 activation occurs independently of STIM1 (Maltan et al. 2023). The Ca2+ channel ORAI1 is a regulator of oral cancer growth and nociceptive pain (Son et al. 2023).

Metazoa, Chordata
Orai1/STIM1 complex of Homo sapiens
Orai1 (Q96D31)
STIM1 (Q13586)

The ARC (Arachidonate-regulated Ca2+-selective) channel, a complex of STIM1, Orai1 and Orai3 (Mignen et al., 2008). It is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits (Mignen et al., 2009). (But see Demuro et al., 2011; 1.A.52.1.1). Molecular determinants within the N-terminus control channel activation and gating (Bergsmann et al., 2011).  Specifically activated by high concentrations (>50 microM) of 2-aminoethyl diphenylborinate (2-APB) (Amcheslavsky et al. 2014).  The CC1-SOAR region of STIM1 is a direct activation domain of temperature, leading to subsequent STIM1 activation, and the transmembrane (TM) region and K domain but not EF-SAM region were needed for this process. Furthermore, both the TM and SOAR domains exhibited similarities and differences between STIM1-mediated thermal sensation and store-operated calcium entry (SOCE), and the key sites of Orai1 showed similar roles in these two responses. Additionally, the TM23 (comprising TM2, loop2, and TM3) region of Orai1 was identified as the key domain determining the STIM1/Orai1 thermal response pattern (Liu et al. 2023).

Metazoa, Chordata
Orai3 of Homo sapiens (Q9BRQ5)

The CRAC channel Orai2 (DUF 1650) (264 aas) (Gross et al., 2007).

Metazoa, Chordata
Orai2 of Mus musculus (Q8BH10)

Insect STIM1/Orai1 (Hull et al., 2010). Influences sex pheromone production in moths. 

Metazoa, Arthropoda
Stim1/Orai1A or B of Bombyx mori 
Stim1 (B5BRC2)
Orai1, splice form A (B5BRC5)
Orai1, splice form B (B5BRC4) 

Ca2+ release-activated Ca2+ (CRAC) channel subunit, Orai, which mediates Ca2+ influx following depletion of intracellular Ca2+ stores.  In Greek mythology, the 'Orai' are the keepers of the gates of heaven.  The crystal structure (3.35 Å), revealed a hexameric assembly of Orai subunits arranged around a central ion pore which traverses the membrane and extends into the cytosol. A ring of glutamate residues on its extracellular side forms the selectivity filter. A basic region near the intracellular side can bind anions that may stabilize the closed state. The architecture of the channel differs from those of other solved ion channels (Hou et al. 2012). Residues in the third TMS of orai affect the conduction properties of the channel (Alavizargar et al. 2018); a conserved glutamate residue (E262) contributes to selectivity. Mutation of this residue affected the hydration pattern of the pore domain, and impaired selectivity of Ca2+ over Na+. The crevices of water molecules are located to contribute to the dynamics of the hydrophobic gate and the basic gate, suggesting a possible role in channel opening and in selectivity function (Alavizargar et al. 2018). 

     The Orai channel is characterized by voltage independence, low conductance, and high Ca2+ selectivity and plays a role in Ca2+ influx through the plasma membrane (PM). Liu et al. 2019 reported the crystal structure and cryo-EM reconstruction of a mutant (P288L) channel that is constitutively active. The open state showed a hexameric assembly in which 6 TMS 1 helices in the center form the ion-conducting pore, and 6 TMS 4 helices in the periphery form extended long helices. Orai channel activation requires conformational transduction from TM4 to TM1 and causes the basic section of TM1 to twist outward. The wider pore on the cytosolic side aggregates anions to increase the potential gradient across the membrane and thus facilitate Ca2+ permeation (Liu et al. 2019).

Metazoa, Arthropoda
Orai (Olf186-F) of Drosophila melanogaster

Orai homologue (494aas; 4 or 5 TMSs)

Viridiplantae, Chlorophyta
Orai homologue in Ostreococcus tauri (Q012G5)

Orai homologue (244aas; 4 TMSs)

Orai homologue in Phytophthora infestans T30-4 (D0NKP9)