Cracking CRAC

Abstract

CRACR2A is a newly discovered Ca²⁺-binding protein that regulates store-operated Ca²⁺ entry (SOCE). CRACR2A enhances SOCE by promoting the binding of the endoplasmic reticulum Ca²⁺ sensor STIM to Orai, a Ca²⁺ channel located in the plasma membrane. As intracellular Ca²⁺ levels rise, CRACR2A binds Ca²⁺ and triggers SOCE inactivation by dissociating from the Orai–STIM complex.

Figure 1

Milestones in the discovery of molecular mechanisms governing SOCE. The figure was provided by Jesus Sanchez (Centro Nacional de Biotecnología, Madrid 28049, Spain).

Figure 2

CRACR2A is a novel component of the STIM1–Orai complex that controls SOCE. (a) Cells in resting conditions, with Ca²⁺ stores filled. (b) Ca²⁺ depletion in the ER triggers STIM clustering and recruitment to ER–plasma membrane junctions. Orai also accumulates in the junctions, where it interacts with STIM and CRACR2A, inducing channel activation. (c) CRACR2A EF-hand domains bind Ca²⁺ and trigger the dissociation of CRACR2A from the Orai/STIM complex. This may promote Ca²⁺/CaM binding to Orai and CRAC inactivation.