1. Neuroscience
  2. Physics of Living Systems
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The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores

  1. Zhenyong Wu
  2. Nadiv Dharan
  3. Zachary A McDargh
  4. Sathish Thiyagarajan
  5. Ben O'Shaughnessy
  6. Erdem Karatekin  Is a corresponding author
  1. University of Wisconsin, United States
  2. Columbia University, United States
  3. Yale University School of Medicine, United States
Research Article
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Cite this article as: eLife 2021;10:e68215 doi: 10.7554/eLife.68215

Abstract

All membrane fusion reactions proceed through an initial fusion pore, including calcium-triggered release of neurotransmitters and hormones. Expansion of this small pore to release cargo is energetically costly and regulated by cells, but the mechanisms are poorly understood. Here we show that the neuronal/exocytic calcium sensor Synaptotagmin-1 (Syt1) promotes expansion of fusion pores induced by SNARE proteins. Pore dilation relied on calcium-induced insertion of the tandem C2 domain hydrophobic loops of Syt1 into the membrane, previously shown to reorient the C2 domain. Mathematical modelling suggests that C2B reorientation rotates a bound SNARE complex so that it exerts force on the membranes in a mechanical lever action that increases the height of the fusion pore, provoking pore dilation to offset the bending energy penalty. We conclude that Syt1 exerts novel non-local calcium-dependent mechanical forces on fusion pores that dilate pores and assist neurotransmitter and hormone release.

Data availability

All data associated with the plots shown in this study are included in the manuscript and supporting files. Source data files have been provided for all figures, in the form of a .zip file containing mostly matlab .fig and/or .mat files corresponding to the data presented in the manuscript and the Appendix. The raw data can be extracted for every plot from the .fig file. In a few cases, we included excel or Igor Pro files.

Article and author information

Author details

  1. Zhenyong Wu

    Department of Neuroscience, University of Wisconsin, Madison, WI, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Nadiv Dharan

    Chemical Engineering, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Zachary A McDargh

    Chemical Engineering, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9022-5593

  4. Sathish Thiyagarajan

    Department of Physics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Ben O'Shaughnessy

    Department of Chemical Engineering, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Erdem Karatekin

    Department of Cellular and Molecular Physiology, Yale University School of Medicine, West Haven, United States
    For correspondence
    erdem.karatekin@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5934-8728

Funding

National Institute of Neurological Disorders and Stroke (R01NS113236)

  • Erdem Karatekin

National Eye Institute (R01EY010542)

  • Erdem Karatekin

National Institute of General Medical Sciences (R01GM117046)

  • Ben O'Shaughnessy

Columbia University (Shared Research Computing Facility)

  • Ben O'Shaughnessy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Felix Campelo, The Barcelona Institute of Science and Technology, Spain

Publication history

  1. Received: March 9, 2021
  2. Accepted: June 29, 2021
  3. Accepted Manuscript published: June 30, 2021 (version 1)
  4. Version of Record published: July 21, 2021 (version 2)

Copyright

© 2021, Wu 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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