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Transmembrane and coiled-coil domains 1 (TMCO1) has a highly conserved amino acid sequence among species, indicating a critical role of TMCO1 in cell physiology. The deficiency of TMCO1 in humans is associated with cerebrofaciothoracic dysplasia (CFTD), glaucoma, osteogenesis and the occurrence of cancer. TMCO1 was recently identified as an endoplasmic reticulum (ER) Ca2+ load-activated Ca2+ (CLAC) release channel, which prevents ER Ca2+ overload and maintains calcium homeostasis in the ER. However, the structural basis of the molecular