A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore
- Northwestern University Feinberg School of Medicine, United States
- Hospital for Sick Children, Canada
- The Hospital for Sick Children, Canada
Abstract
Sulfur-aromatic interactions occur in the majority of protein structures, yet little is known about their functional roles in ion channels. Here, we describe a novel molecular motif, the M101 gate latch, which is essential for gating of human Orai1 channels via its sulfur-aromatic interactions with the F99 hydrophobic gate. Molecular dynamics simulations of different Orai variants reveal that the gate latch is engaged in open but not in closed channels. In experimental studies, we use metal ion bridges to show that promoting an M101-F99 bond directly activates Orai1, whereas disrupting this interaction triggers channel closure. Mutational analysis demonstrates that methionine at this position has a unique length, flexibility, and chemistry to act as an effective latch for the phenylalanine gate. Because sulfur-aromatic interactions provide additional stabilization compared to purely hydrophobic interactions, we postulate that the six M101-F99 pairs in the hexameric channel represent a substantial energetic contribution to Orai1 activation.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (NS057499)
- Murali Prakriya
National Institutes of Health (F31NS101830)
- Priscilla S-W Yeung
Canadian Institutes of Health Research (MOP130461)
- Régis Pomès
National Institutes of Health (GM114210)
- Murali Prakriya
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Yeung 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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A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore
eLife 9:e60751.
https://doi.org/10.7554/eLife.60751
