TMCO1 Is An ER Ca2+ Load-Activated Ca2+ Channel
Maintaining 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.
Wang, Qiao Chu; Zheng, Qiaoxia; Tan, Haiyan; Zhang, Bing; Li, Xiaoling; Yang, Yuxiu; Yu, Jie; Liu, Yang; Chai, Hao; Wang, Xi; Sun, Zhongshuai; Wang, Jiu Qiang; Zhu, Shu; Wang, Fengli; Yang, Maojun; Guo, Caixia; Wang, Heng; Zheng, Qingyin; Li, Yang; Chen, Quan; Zhou, Aimin; and Tang, Tie Shan, "TMCO1 Is An ER Ca2+ Load-Activated Ca2+ Channel" (2016). Chemistry Faculty Publications. 457.