Fig. 4.

Schematic representation of the four steps that define the STIM1 ER-to-PM signaling relay. (Left) When ER stores are loaded with Ca²⁺, Ca²⁺ is bound to the EF hand of STIM1, preventing STIM1 oligomerization. (Center) In the first two activation steps, a reduction in luminal ER Ca²⁺ leads to Ca²⁺ dissociation from the EF hand, which triggers a rapid oligomerization of STIM1. The oligomerization of STIM1 exposes the C-terminal polybasic PM-targeting motif. (Right) In the next two steps, STIM1 oligomers are recruited via diffusion along the ER network to nearby ER–PM junctions where STIM1 interacts with the PM Ca²⁺ channel Orai1 and activates SOC influx.