Document Type

Article

Publication Date

2016

Publication Title

Cell

Abstract

Maintaining homeostasis of Ca2+stores in theendoplasmic reticulum (ER) is crucial for properCa2+signaling and key cellular functions. The Ca2+-release-activated Ca2+(CRAC) channel is respon-sible for Ca2+influx and refilling after store depletion,but how cells cope with excess Ca2+when ER storesare overloaded is unclear. We show that TMCO1 is anER transmembrane protein that actively preventsCa2+stores from overfilling, acting as what we terma ‘‘Ca2+load-activated Ca2+channel’’ or ‘‘CLAC’’channel. TMCO1 undergoes reversible homotetra-merization in response to ER Ca2+overloadingand disassembly upon Ca2+depletion and forms aCa2+-selective ion channel on giant liposomes.TMCO1 knockout mice reproduce the main clinicalfeatures of human cerebrofaciothoracic (CFT)dysplasia spectrum, a developmental disorder linkedto TMCO1 dysfunction, and exhibit severe mishan-dling of ER Ca2+in cells. Our findings indicate thatTMCO1 provides a protective mechanism to preventoverfilling 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).

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

DOI

10.1016/j.cell.2016.04.051

Version

Postprint

Volume

165

Issue

6

Included in

Chemistry Commons

Share

COinS