Molecular anatomy of the early events in STIM1 activation - oligomerization or conformational change?

Decreased luminal endoplasmic reticulum (ER) Ca²⁺ concentration triggers oligomerization and clustering of the ER Ca²⁺ sensor STIM1 to promote its association with plasma membrane Orai1 Ca²⁺ channels leading to increased Ca²⁺ influx. A key step in STIM1 activation is the release of its SOAR domain from an intramolecular clamp formed with the STIM1 first coiled-coil (CC1) region. Using a truncated STIM1(1-343) molecule that captures or releases the isolated SOAR domain depending on luminal ER Ca²⁺ concentrations, we analyzed the early molecular events that control the intramolecular clamp formed between the CC1 and SOAR domains. We found that STIM1 forms constitutive dimers, and its CC1 domain can bind the SOAR domain of another STIM1 molecule in trans. Artificial oligomerization failed to liberate the SOAR domain or activate STIM1 unless the luminal Ca²⁺-sensing domains were removed. We propose that the release of SOAR from its CC1 interaction is controlled by changes in the orientation of the two CC1 domains in STIM1 dimers. Ca²⁺ unbinding in the STIM1 luminal domains initiates the conformational change allowing SOAR domain liberation and clustering, leading to Orai1 channel activation.