TMCO1 Is an ER Ca2+ Load-Activated Ca2+ Channel

•TMCO1 gene encodes an evolutionarily conserved ER transmembrane-spanning protein•Loss of TMCO1 causes overloading of ER Ca2+ store and mishandling of Ca2+ signaling•TMCO1 assembles into a Ca2+ selective channel in response to ER Ca2+ overloading•Ca2+ channel function of TMCO1 is disrupted by CFT dysplasia spectrum mutations

SummaryMaintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. The Ca2+-release-activated Ca2+ (CRAC) channel is responsible for Ca2+ influx and refilling after store depletion, but how cells cope with excess Ca2+ when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca2+ stores from overfilling, acting as what we term a “Ca2+ load-activated Ca2+ channel” or “CLAC” channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca2+ overloading and disassembly upon Ca2+ depletion and forms a Ca2+-selective ion channel on giant liposomes. TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca2+ in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca2+ ions.

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