1.A.52.1.5
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).