| Title: |
TMCO1 Is an ER Ca2+ Load-Activated Ca2+ Channel |
| Author: |
Qiao-Chu Wang, Qiaoxia Zheng, Haiyan Tan, Bing Zhang, Xiaoling Li, Yuxiu Yang, Jie Yu, Yang Liu, Hao Chai, Xi Wang, Zhongshuai Sun, Jiu-Qiang Wang, Shu Zhu, Fengli Wang, Maojun Yang, Caixia Guo, Heng Wang, Qingyin Zheng, Yang Li, Quan Chen, Aimin Zhou, Tie-Shan Tang |
| Abstract: |
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. |
| Corresponding author: |
Zhou Aimin, Tang Tieshan |
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| PubYear: |
2016 |
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DOI: 10.1016/j.cell.2016.04.051 |
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| Journal: |
Cell |
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