Structures reveal opening of the store-operated calcium channel Orai
- Memorial Sloan Kettering Cancer Center, United States
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.
Data availability
Atomic coordinates, structure factors, and crystallographic phases have been deposited in the Protein Data Bank with accession numbers 6BBF (H206A Oraicryst), 6BBG (WT Oraicryst), 6BBH (K163W Oraicryst, I41 form), and 6BBI (K163W Oraicryst, P42212 form)
Article and author information
Author details
Stephen Barstow Long
Funding
National Institutes of Health (R01 GM094273)
- Stephen Barstow Long
National Institutes of Health (P30 CA008748)
- Stephen Barstow Long
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Hou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structures reveal opening of the store-operated calcium channel Orai
eLife 7:e36758.
https://doi.org/10.7554/eLife.36758
