Structures reveal opening of the store-operated calcium channel Orai

Abstract
Data availability
Article and author information
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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)

The following data sets were generated

1. Hou X
2. Burstein S
3. Long SB
(2018) H206A Oraicryst
6BBF.

https://www.rcsb.org/
1. Hou X
2. Burstein S
3. Long SB
(2018) WT Oraicryst
6BBG.

https://www.rcsb.org/
1. Hou X
2. Burstein S
3. Long SB
(2018) K163W Oraicryst, I41 form
6BBH.

https://www.rcsb.org/
1. Hou X
2. Burstein S
3. Long SB
(2018) K163W Oraicryst, P42212 form
6BBI.

https://www.rcsb.org/

Article and author information

Author details

Xiaowei Hou

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Shana R Burstein

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Stephen Barstow Long

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

For correspondence
longs@mskcc.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8144-1398

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

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.