Format

Send to

Choose Destination
Cell. 2016 Jun 2;165(6):1454-1466. doi: 10.1016/j.cell.2016.04.051. Epub 2016 May 19.

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

Author information

1
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
2
Department of Chemistry and the Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA.
3
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
5
Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
6
DDC Clinic, Center for Special Needs Children, Middlefield, OH 44062, USA.
7
Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
8
Department of Chemistry and the Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA. Electronic address: a.zhou@csuohio.edu.
9
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: tangtsh@ioz.ac.cn.

Abstract

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.

PMID:
27212239
PMCID:
PMC4905584
[Available on 2017-06-02]
DOI:
10.1016/j.cell.2016.04.051
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center