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Exploring the conformational changes of the Munc18-1/syntaxin 1a complex

View ORCID ProfileIoanna Stefani, View ORCID ProfileJustyna Iwaszkiewicz, View ORCID ProfileDirk Fasshauer
doi: https://doi.org/10.1101/2022.11.29.518383
Ioanna Stefani
1Department of Computational Biology, University of Lausanne, Génopode, 1015 Lausanne, Switzerland
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Justyna Iwaszkiewicz
2Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland
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Dirk Fasshauer
1Department of Computational Biology, University of Lausanne, Génopode, 1015 Lausanne, Switzerland
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  • For correspondence: dirk.fasshauer@unil.ch
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Abstract

Neurotransmitters are released from synaptic vesicles, the membrane of which fuses with the plasma membrane upon calcium influx. This membrane fusion reaction is driven by the formation of a tight complex comprising the plasma membrane SNARE proteins syntaxin-1a and SNAP-25 with the vesicle SNARE protein synaptobrevin. The neuronal protein Munc18-1 forms a stable complex with syntaxin-1a. Biochemically, syntaxin-1a cannot escape the tight grip of Munc18-1, so formation of the SNARE complex is inhibited. However, Munc18-1 is essential for the release of neurotransmitters in vivo. It has therefore been assumed that Munc18-1 makes the bound syntaxin-1a available for SNARE complex formation. Exactly how this occurs is still unclear, but it is assumed that structural rearrangements occur. Here, we used a series of mutations to specifically weaken the complex at different critical positions in order to induce these rearrangements biochemically. Our approach was guided through sequence and structural analysis and supported by molecular dynamics simulations. Subsequently, we created a homology model showing the complex in an altered conformation. This conformation presumably represents a more open arrangement of syntaxin-1a that permits the formation of SNARE complex to be initiated while still bound to Munc18-1. In the future, research should investigate how this central reaction for neuronal communication is controlled by other proteins.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://zenodo.org/record/7354961#.Y4Y7CC8w2mI

  • List of abbreviations

    (SNAREs)
    N-ethylmaleimide-sensitive factor attachment receptors
    (CATCHR)
    complex associated with tethering containing helical rods
    (SAXS)
    Small-angle X-ray scattering
    (SM)
    Sec1/Munc18
    (MD)
    molecular dynamics
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    Posted November 29, 2022.
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    Exploring the conformational changes of the Munc18-1/syntaxin 1a complex
    Ioanna Stefani, Justyna Iwaszkiewicz, Dirk Fasshauer
    bioRxiv 2022.11.29.518383; doi: https://doi.org/10.1101/2022.11.29.518383
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    Exploring the conformational changes of the Munc18-1/syntaxin 1a complex
    Ioanna Stefani, Justyna Iwaszkiewicz, Dirk Fasshauer
    bioRxiv 2022.11.29.518383; doi: https://doi.org/10.1101/2022.11.29.518383

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