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Two successive oligomeric Munc13 assemblies scaffold vesicle docking and SNARE assembly to support neurotransmitter release

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Listed:
  • Manindra Bera

    (Yale University)

  • Kirill Grushin

    (Yale University)

  • R. Venkat Kalyana Sundaram

    (Yale University)

  • Jasmine S. Hinzen

    (Weill Cornell Medicine)

  • Joyce Chen

    (Weill Cornell Medicine)

  • Atrouli Chatterjee

    (Yale University)

  • Abhijith Radhakrishnan

    (Yale University)

  • Seong Lee

    (Yale University)

  • Murugesh Padmanarayana

    (Weill Cornell Medicine)

  • Jeff Coleman

    (Yale University)

  • Frédéric Pincet

    (Yale University
    Université Paris-Cité)

  • James E. Rothman

    (Yale University)

  • Jeremy S. Dittman

    (Weill Cornell Medicine)

Abstract

The critical protein Munc13 serves numerous roles in the docking and priming of synaptic vesicles. On the presynaptic plasma membrane, Munc13 is organized into nanoclusters corresponding to release sites where synaptic vesicles dock and fuse. However, it is currently not known whether there is any organization of Munc13 monomers within the nanoclusters. Recent work suggests that Munc13 may spontaneously self-organize into homo-oligomers, raising the possibility that synaptic nanoclusters comprise organized assemblies of Munc13. Here we investigate the functional impact of two distinct Munc13 core domain oligomers comprising C1-C2B-MUN-C2C both in vitro and in vivo. Interface mutations that specifically destabilized oligomeric assemblies of Munc13 disrupted vesicle docking, trans-SNARE formation, and Ca2+-triggered vesicle fusion in vitro and impaired neurotransmitter secretion and motor nervous system function in vivo. We suggest that a sequence of oligomeric Munc13 complexes rapidly couple vesicle docking to vesicle priming via the assembly of a precise number of SNAREs.

Suggested Citation

  • Manindra Bera & Kirill Grushin & R. Venkat Kalyana Sundaram & Jasmine S. Hinzen & Joyce Chen & Atrouli Chatterjee & Abhijith Radhakrishnan & Seong Lee & Murugesh Padmanarayana & Jeff Coleman & Frédéri, 2025. "Two successive oligomeric Munc13 assemblies scaffold vesicle docking and SNARE assembly to support neurotransmitter release," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62420-7
    DOI: 10.1038/s41467-025-62420-7
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