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

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

  • Cell. 2016 Jun 2;165(6):1454-1466. doi: 10.1016/j.cell.2016.04.051.
Qiao-Chu Wang 1,  Qiaoxia Zheng 1,  Haiyan Tan 2,  Bing Zhang 3,  Xiaoling Li 1,  Yuxiu Yang 3,  Jie Yu 4,  Yang Liu 5,  Hao Chai 3,  Xi Wang 1,  Zhongshuai Sun 5,  Jiu-Qiang Wang 1,  Shu Zhu 1,  Fengli Wang 1,  Maojun Yang 4,  Caixia Guo 5,  Heng Wang 6,  Qingyin Zheng 7,  Yang Li 3,  Quan Chen 1,  Aimin Zhou 8,  Tie-Shan Tang 9
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
PMID: 27212239 DOI: 10.1016/j.cell.2016.04.051
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.

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