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
  • 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.