FIGURE 2.

Cartoon model of ER–PM junction (store-operated Ca²⁺ entry system pathway). (A) Orai’s monomeric structure: TM1-4 and its C- and N-terminal endings facing the cytosol. (B) Orai channel structure: The channel is conformed by six subunits (monomers) which interact with each other due to the hydrophobic cluster (E106, V102, F99, R91) in their respective TM1. These interactions leave the ion pore at the center of the channel, and it is also stabilized by the TM1–TM2 turret, causing the channel’s selectivity. (C) STIM1 resting state: This protein seems to dimerize in basal conditions. STIM1 monomer’s structure consists of the EF-SAM calcium sensor, facing the ER-lumen, the TM domain, and the CC1, SOAR/CAD segments oriented to the cytosol. The STIM1 monomer in the presence of calcium is folded into the cytosol domain due to hydrophobic interactions between the coiled coils. (D) STIM1 extended state: STIM1 interacts with EB1 protein, helping to remodel the ER and forming STIM1 clusters near the PM; its polybasic tail also seems to interact with the PM. When there is a Ca²⁺ depletion in the ER lumen, STIM1 suffers a conformational change, and both monomers release its SOAR/CAD segments, which, in turn, interact with Orai. (E) Possible activation of Orai: STIM1 could contribute to either rotate Orai’s helices or help the subunits’ outward movement. Orai loses its high permeability and allows the entry of extracellular calcium. TM, transmembrane helices; EF-SAM, EF hand 1, non-canonical ER hand 2, and sterile alfa motile; CC1, coiled coil 1; SOAR/CAD, Stim1-Orai1 activating region/CRAC activation domain; EB1, microtubule plus-end tracking of end binding protein 1; cyt, cytosol; ER, endoplasmic reticulum; PM, plasma membrane.