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Munc13- and SNAP25-dependent molecular bridges play a key role in synaptic vesicle priming

2023; American Association for the Advancement of Science; Volume: 9; Issue: 25 Linguagem: Inglês

10.1126/sciadv.adf6222

2375-2548

Christos Papantoniou, Ulrike Laugks, Julia Betzin, Cristina Capitanio, José Javier Ferrero, José Sánchez‐Prieto, Susanne Schoch, Nils Brose, Wolfgang Baumeister, Benjamin H. Cooper, Cordelia Imig, Vladan Lučić,

Neuroscience and Neuropharmacology Research

Synaptic vesicle tethering, priming, and neurotransmitter release require a coordinated action of multiple protein complexes. While physiological experiments, interaction data, and structural studies of purified systems were essential for our understanding of the function of the individual complexes involved, they cannot resolve how the actions of individual complexes integrate. We used cryo-electron tomography to simultaneously image multiple presynaptic protein complexes and lipids at molecular resolution in their native composition, conformation, and environment. Our detailed morphological characterization suggests that sequential synaptic vesicle states precede neurotransmitter release, where Munc13-comprising bridges localize vesicles <10 nanometers and soluble N-ethylmaleimide-sensitive factor attachment protein 25-comprising bridges <5 nanometers from the plasma membrane, the latter constituting a molecularly primed state. Munc13 activation supports the transition to the primed state via vesicle bridges to plasma membrane (tethers), while protein kinase C promotes the same transition by reducing vesicle interlinking. These findings exemplify a cellular function performed by an extended assembly comprising multiple molecularly diverse complexes.