Panel A: A linear diagram of the Orai1 protein domain structure, showing the locations of ETON, TM1, TM2, TM3, TM4, and the C-terminus. Panel B: A schematic representation of an Orai1 subunit, illustrating four transmembrane helices (TM1-TM4), cytosolic N- and C-termini, and intracellular and extracellular loops. Panel C: A top view of the Orai1 hexameric channel, displaying the arrangement of the six TM1 helices forming the pore, the inner interface composed of TM1, TM2, and TM3 helices, and the outer interface formed by TM2, TM3, and TM4 helices. Panel D: A side view of two Orai1 subunits, highlighting the selectivity filter, hydrophobic region, and basic region within the channel pore. Panel E: A diagram of Orai1 with disease-causing gain-of-function (GoF) mutations marked in red. Panel F: A diagram of Orai1 with disease-causing loss-of-function (LoF) mutations that do not affect channel expression or trafficking, marked in blue. Panel G: A diagram of Orai1 with disease-causing LoF variants resulting from premature translation termination, marked in light blue, and variants causing LoF due to reduced channel stability or trafficking defects, marked in turquoise. Mutations marked with an asterisk occur in patients only in combination with other mutants, and bold and cursive mutations differ from a simple GoF or LoF phenotype.
Schematic insight into the structure of Orai1 and location of disease-causing mutants. (A) Domain structure of Orai1. (B) Schematic representation of an Orai1 subunit. Each subunit has 4 TM helices TM1–TM4, cytosolic N and C termini, an intracellular loop, and two extracellular loops. (C) Top view showing the arrangement of the Orai1 hexameric channel. The six TM1 helices form the pore of the channel (light green). The TM1 helices together with the TM2 and TM3 helices constitute the inner interface (middle green). The TM2/3 helices together with TM4 form the outer interface (dark green). (D) Side view of two Orai1 subunits. The pore of the channel can be divided into three functional regions: the selectivity filter at the pore entrance, followed by a hydrophobic region and a basic region toward the cytosolic side. (E) Disease-causing GoF mutations found in Orai1 (red). (F) Disease-causing LoF Orai1 mutants that leave channel expression and trafficking unaffected (blue). (G) Disease-causing Orai1 LoF variants resulting from premature translation termination, leading to impaired expression or trafficking, are shown in light blue. Orai1 variants that cause LoF due to reduced channel stability or trafficking defects are shown in turquoise. Mutations marked with * occur in patients only in combination with other mutants, and bold and cursive written mutations differ from a simple GoF or LoF phenotype.