ArticleeLife2020
A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- Optical single-channel recording of CRAC channels with HaloTag and a CabioRxiv : the preprint server for biology · 2026Article
- Regulation of neuropathic pain by microglial Orai1 channels.Science advances · 2023Article
- Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers.Biomolecules · 2021Article
- Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology.International journal of molecular sciences · 2021Review
- Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity.Biomolecules · 2021Article
- The Orai Pore Opening Mechanism.International journal of molecular sciences · 2021Review
- Interrogating permeation and gating of Orai channels using chemical modification of cysteine residues.Methods in enzymology · 2021Article
- CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions.The Journal of biological chemistryArticle
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5 authors.
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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 mostly engaged in open but not 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 the methionine residue at this position has a unique combination of 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 infer that the six M101-F99 pairs in the hexameric channel provide a substantial energetic contribution to Orai1 activation.
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