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Title: Structures reveal opening of the store-operated calcium channel Orai

Abstract

The store-operated calcium (Ca2+) channel Orai governs Ca2+ influx through the plasma membrane of many non-excitable cells in metazoans. The channel opens in response to the depletion of Ca2+ stored in the endoplasmic reticulum (ER). Loss- and gain-of-function mutants of Orai cause disease. Our previous work revealed the structure of Orai with a closed pore. Here, using a gain-of-function mutation that constitutively activates the channel, we present an X-ray structure of Drosophila melanogaster Orai in an open conformation. Well-defined electron density maps reveal that the pore is dramatically dilated on its cytosolic side in comparison to the slender closed pore. Cations and anions bind in different regions of the open pore, informing mechanisms for ion permeation and Ca2+ selectivity. Opening of the pore requires the release of cytosolic latches. Together with additional X-ray structures of an unlatched-but-closed conformation, we propose a sequence for store-operated activation.

Authors:
 [1];  [1]; ORCiD logo [1]
  1. Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1477115
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 7; Journal Issue: 2018; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Hou, Xiaowei, Burstein, Shana R., and Long, Stephen Barstow. Structures reveal opening of the store-operated calcium channel Orai. United States: N. p., 2018. Web. doi:10.7554/eLife.36758.
Hou, Xiaowei, Burstein, Shana R., & Long, Stephen Barstow. Structures reveal opening of the store-operated calcium channel Orai. United States. doi:10.7554/eLife.36758.
Hou, Xiaowei, Burstein, Shana R., and Long, Stephen Barstow. Thu . "Structures reveal opening of the store-operated calcium channel Orai". United States. doi:10.7554/eLife.36758.
@article{osti_1477115,
title = {Structures reveal opening of the store-operated calcium channel Orai},
author = {Hou, Xiaowei and Burstein, Shana R. and Long, Stephen Barstow},
abstractNote = {The store-operated calcium (Ca2+) channel Orai governs Ca2+ influx through the plasma membrane of many non-excitable cells in metazoans. The channel opens in response to the depletion of Ca2+ stored in the endoplasmic reticulum (ER). Loss- and gain-of-function mutants of Orai cause disease. Our previous work revealed the structure of Orai with a closed pore. Here, using a gain-of-function mutation that constitutively activates the channel, we present an X-ray structure of Drosophila melanogaster Orai in an open conformation. Well-defined electron density maps reveal that the pore is dramatically dilated on its cytosolic side in comparison to the slender closed pore. Cations and anions bind in different regions of the open pore, informing mechanisms for ion permeation and Ca2+ selectivity. Opening of the pore requires the release of cytosolic latches. Together with additional X-ray structures of an unlatched-but-closed conformation, we propose a sequence for store-operated activation.},
doi = {10.7554/eLife.36758},
journal = {eLife},
issn = {2050-084X},
number = 2018,
volume = 7,
place = {United States},
year = {2018},
month = {8}
}