title: TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.
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.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qiao-Chu
authors.initials: QC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qiaoxia
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and the Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tan
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chai
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhongshuai
authors.initials: Z
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiu-Qiang
authors.initials: JQ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Maojun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.affiliation: DDC Clinic, Center for Special Needs Children, Middlefield, OH 44062, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D015220:Calcium Channels; C000612072:TMCO1 protein, mouse; D002118:Calcium