Figure 1. Regulation of STIM1 activation by STIMATE.

When the ER is replete with Ca²⁺ (left) resting STIM1 exists as a dimer with Ca²⁺ bound to its luminal EF-hands and in a folded conformation with SOAR closely associated with CC1. STIMATE is located in the ER membrane, available to modulate STIM1 activation. As ER luminal Ca²⁺ levels decrease (middle), Ca²⁺ dissociates from the EF-hands of STIM, resulting in a conformational change that promotes binding between STIMATE and CC1. This relieves inhibition of SOAR, leading to transformation of STIM1 into fully activated, unfolded conformation (right). STIM1 can then translocate to ER-PM junctions where it can facilitate SOCE. [inset] Identification of STIM1 domains. Poly-K - Lysine-rich domain; SOAR – STIM-Orai1 Activating Region; CC1 – Coiled-coil 1; TM – Transmembrane domain; SAM – Sterile α motif; cEF – canonical EF hand; hEF – homologous EF hand.