Fig. 1.

Functional domains and human mutations in ORAI1 and STIM1. a ORAI1 contains four transmembrane domains (M1–4) with the alpha-helical M1 lining the calcium release activated calcium (CRAC) channel pore [84]. Putative Ca²⁺-binding glutamate and as-partate residues (E106, D110, and D112) [114, 141, 155], a calmodulin binding domain (CBD) [89], a coiled-coil domain (CC) containing a leucine residue (L273) critical for STIM1 binding [88], and a glycosylation site in the second extracellular loop (N223) [49] are shown. Mutations affecting ORAI1 function or protein expression in human patients are indicated in red (for details, see text) [40, 82]. b STIM1 contains an N-terminal Ca²⁺ binding EF hand domain and a sterile alpha motif (SAM) both of which are localized in the ER; the cytoplasmic C terminus comprises two coiled-coil (CC), a serine/proline rich (S/P), and a polybasic lysine-rich (K) domain. A minimal CRAC channel binding and activation domain (alternatively termed CRAC channel activation domain (CAD), STIM1 Orai activating region (SOAR), Orai1 activating small fragment (OASF), and coiled-coil fragment b9 (CCb9) [63, 87, 103, 157] and an adjacent CRAC modulatory domain (CMD) [28, 69, 89] are shown. The position of a frameshift nonsense mutation abolishing STIM1 expression in human patients is indicated in red (for details see text) [110]