Orai channels are pore forming proteins which underlie calcium release-activated calcium (CRAC) channels ^[1]. Orai channels have 4 transmembrane (TM) helices, of which the C-terminal innermost TM1 is the pore-forming helix, and the outermost TM4 extension (TM4e) provides a strong binding site for SOAR ^[2]. Orai1 is a 301 amino acid protein that is expressed on the plasma membrane of most cell types. Orai1 is predicted to have four transmembrane domains, with N and C termini as well as a single loop within the cytoplasmic space ^[3].

The N-terminal Calmodulin (CaM) Binding Domain of Orai1 (CBDOrai1, aa. 68–91) binds CaM in a Ca²⁺-dependent manner. Mutations of the CBDOrai1 that prevent CaM binding, e.g. A73E, W76A, W76E, W76S and Y80E, result in currents with reduced FCDI and prominent reactivation in response to hyperpolarising steps. In contrast, mutations of the CBDOrai1 that retained CaM binding, Y80A and Y80S, enhance FCDI ^[3]. co-transfection of STIM1 and Orai1 with residues 151–154 within the loop mutated to alanine results in an increase in whole cell current amplitude in response to store depletion ^[4]. A region of the Orai1 C terminus, identified as aa. 268–291, containing a series of charged residues has shown by immunoprecipitation and yeast two-hybrid assays to interact with STIM1-CAD ^[5].

E106 of Orai1 in TM1 was identified as the CRAC channel selectivity centre. Mutations of E106 of Orai1 to glutamine (E106Q) or alanine (E106A) have a dominant negative effect, suppressing any WT CRAC current ^[6,7,8] A V102I mutation of Orai1 was reported to potentiate ICRAC in response to hyperpolarising steps both in the presence and absence of Ca²⁺. Since this potentiation was independent from the extracellular ion composition, it was suggested that this mutation introduces a slow voltage gate due to interaction of the V102I residue with a gating charge at the selectivity filter, presumably at E106 ^[9].