Journal
CELL
Volume 165, Issue 6, Pages 1454-1466Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.04.051
Keywords
-
Categories
Funding
- National Basic Research Program of China [2012CB944702, NSFC 81371415, 91519324, 31570816, 31401151, 81300982]
- Ohio Research Scholars Program
- Faculty Research and Development Program of Cleveland State University
- [2013CB91060101]
- [3137106601]
- [3117101101]
- [2012ZX09301]
- [2011CB910502]
- [2012CB911101]
- [NSFC 31030020]
- [31170679]
- [2013CB945003]
- [31471331]
- [XDB14030302]
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Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. The Ca2+-release-activated Ca2+ (CRAC) channel is responsible for Ca2+ influx and refilling after store depletion, but how cells cope with excess Ca2+ when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca2+ stores from overfilling, acting as what we term a Ca2+ load-activated Ca2+ channel or CLAC channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca2+ overloading and disassembly upon Ca2+ depletion and forms a Ca2+-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 Ca2+ in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca2+ ions.
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