TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel

Maintaining homeostasis of Ca(2+) stores in the endoplasmic reticulum (ER) is crucial for proper Ca(2+) signaling and key cellular functions. The Ca(2+)-release-activated Ca(2+) (CRAC) channel is responsible for Ca(2+) influx and refilling after store depletion, but how cells cope with excess Ca(2+)...

Full description

Saved in:
Bibliographic Details
Published in:Cell 2016-06, Vol.165 (6), p.1454-1466
Main Authors: 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, Tang, Tie-Shan
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Ataxia - genetics
Calcium - metabolism
Calcium Channels - genetics
Calcium Channels - metabolism
Chlorocebus aethiops
COS Cells
Endoplasmic Reticulum - metabolism
HEK293 Cells
HeLa Cells
Humans
Intellectual Disability - genetics
Intracellular Membranes - metabolism
Mice
Mice, Knockout
Osteogenesis - genetics
Sequence Alignment
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Maintaining homeostasis of Ca(2+) stores in the endoplasmic reticulum (ER) is crucial for proper Ca(2+) signaling and key cellular functions. The Ca(2+)-release-activated Ca(2+) (CRAC) channel is responsible for Ca(2+) influx and refilling after store depletion, but how cells cope with excess Ca(2+) when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca(2+) stores from overfilling, acting as what we term a "Ca(2+) load-activated Ca(2+) channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca(2+) overloading and disassembly upon Ca(2+) depletion and forms a Ca(2+)-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 Ca(2+) in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca(2+) ions.
ISSN:1097-4172
DOI:10.1016/j.cell.2016.04.051