1. Structural Biology and Molecular Biophysics

A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore

  1. Priscilla S-W Yeung
  2. Christopher E Ing
  3. Megumi Yamashita
  4. Régis Pomès
  5. Murali Prakriya  Is a corresponding author
  1. Northwestern University Feinberg School of Medicine, United States
  2. Hospital for Sick Children, Canada
  3. The Hospital for Sick Children, Canada
https://doi.org/10.7554/eLife.60751
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  1. Priscilla S-W Yeung
  2. Christopher E Ing
  3. Megumi Yamashita
  4. Régis Pomès
  5. Murali Prakriya
(2020)
A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore
eLife 9:e60751.
https://doi.org/10.7554/eLife.60751
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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 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.

Article and author information

Author details

  1. Priscilla S-W Yeung

    Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Christopher E Ing

    Molecular Structure and Function, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6947-5731

  3. Megumi Yamashita

    Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Régis Pomès

    Molecular Structure and Function, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3068-9833

  5. Murali Prakriya

    Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
    For correspondence
    m-prakriya@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0781-4480

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.

Reviewing Editor

  1. Richard S Lewis, Stanford University School of Medicine, United States

Version history

  1. Received: July 6, 2020
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: October 30, 2020 (version 1)
  4. Version of Record published: November 20, 2020 (version 2)

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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  1. Priscilla S-W Yeung
  2. Christopher E Ing
  3. Megumi Yamashita
  4. Régis Pomès
  5. Murali Prakriya
(2020)
A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore
eLife 9:e60751.
https://doi.org/10.7554/eLife.60751

Share this article

https://doi.org/10.7554/eLife.60751

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