TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.
- Authors
- Wang, Q.C., Zheng, Q., Tan, H., Zhang, B., Li, X., Yang, Y., Yu, J., Liu, Y., Chai, H., Wang, X., Sun, Z., Wang, J.Q., Zhu, S., Wang, F., Yang, M., Guo, C., Wang, H., Zheng, Q., Li, Y., Chen, Q., Zhou, A., Tang, T.S.
- ID
- ZDB-PUB-170525-10
- Date
- 2016
- Source
- Cell 165(6): 1454-66 (Journal)
- Registered Authors
- Li, Yang
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Ataxia/genetics
- COS Cells
- Calcium/metabolism
- Calcium Channels/genetics
- Calcium Channels/metabolism*
- Chlorocebus aethiops
- Endoplasmic Reticulum/metabolism*
- HEK293 Cells
- HeLa Cells
- Humans
- Intellectual Disability/genetics
- Intracellular Membranes/metabolism
- Mice
- Mice, Knockout
- Osteogenesis/genetics
- Sequence Alignment
- PubMed
- 27212239 Full text @ Cell
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.