Background: Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a
diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis.
The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated
Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two
proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic
reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC
channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant
CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this
Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic
target of CRAC channels provides the space for a new approach to treat autoimmune disorders.
Objective: This review aims to provide the key structural and mechanical insights of STIM1, ORAI1
and other molecular modulators involved in CRAC channel regulation.
Results and Conclusion: Understanding the structure and function of the protein is the foremost step
towards improving the effective target specificity by limiting their potential side effects. Herein, the
review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along
with its biophysical properties that would provide the solid foundation to aid the development of novel
targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations
in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized.