Title

TMCO1 Is An ER Ca2+ Load-Activated Ca2+ Channel

Document Type

Article

Publication Date

6-2-2016

Publication Title

Cell

Abstract

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.

Comments

This work was supported by grants to T.-S.T. (National Basic Research Program of China 2012CB944702; NSFC 81371415, 91519324, 31570816, 31401151, and 81300982), A.Z. (awards from the Ohio Research Scholars Program and the Faculty Research and Development Program of Cleveland State University), Y. Li (2013CB91060101, 3137106601, 3117101101, and 2012ZX09301), M.Y. (2011CB910502, 2012CB911101, NSFC 31030020, and 31170679), and C.G. (2013CB945003, 31471331, and XDB14030302).

DOI

10.1016/j.cell.2016.04.051

Volume

165

Issue

6