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

Manindra Bera; Kirill S. Grushin; Ramalingam Venkat Kalyana Sundaram; Jasmine Shahanoor Hinzen; Joyce Chen; Atrouli Chatterjee; Abhijith Radhakrishnan; Seong Lee; Murugesh Padmanarayana; Jeff Coleman; Frédéric Pincet; James E. Rothman; Jeremy S. Dittman

doi:10.1038/s41467-025-62420-7

NeuroscienceNature CommunicationsAug 5, 2025

Peer-reviewed journal article

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

Manindra Bera iD, Kirill S. Grushin iD, Ramalingam Venkat Kalyana Sundaram iD, Jasmine Shahanoor Hinzen, Joyce Chen iD, Atrouli Chatterjee iD, Abhijith Radhakrishnan iD, Seong Lee, Murugesh Padmanarayana iD, Jeff Coleman iD, Frédéric Pincet iD, James E. Rothman iD, Jeremy S. Dittman iD

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Abstract

The critical presynaptic protein Munc13 serves numerous roles in the process of docking and priming synaptic vesicles. Here we investigate the functional significance of two distinct oligomers of the Munc13 core domain (Munc13C) comprising C1-C2B-MUN-C2C. Oligomer interface point mutations that specifically destabilized either the trimer or lateral hexamer assemblies of Munc13C 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 progression of oligomeric Munc13 complexes couples vesicle docking and assembly of a precise number of SNARE molecules to support rapid and high-fidelity vesicle priming.