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-Structure paper
Title | Munc13 structural transitions and oligomers that may choreograph successive stages in vesicle priming for neurotransmitter release. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 119, Issue 7, Year 2022 |
Publish date | Feb 15, 2022 |
Authors | Kirill Grushin / R Venkat Kalyana Sundaram / Charles V Sindelar / James E Rothman / |
PubMed Abstract | How can exactly six SNARE complexes be assembled under each synaptic vesicle? Here we report cryo-EM crystal structures of the core domain of Munc13, the key chaperone that initiates SNAREpin ...How can exactly six SNARE complexes be assembled under each synaptic vesicle? Here we report cryo-EM crystal structures of the core domain of Munc13, the key chaperone that initiates SNAREpin assembly. The functional core of Munc13, consisting of C1-C2B-MUN-C2C (Munc13C) spontaneously crystallizes between phosphatidylserine-rich bilayers in two distinct conformations, each in a radically different oligomeric state. In the open conformation (state 1), Munc13C forms upright trimers that link the two bilayers, separating them by ∼21 nm. In the closed conformation, six copies of Munc13C interact to form a lateral hexamer elevated ∼14 nm above the bilayer. Open and closed conformations differ only by a rigid body rotation around a flexible hinge, which when performed cooperatively assembles Munc13 into a lateral hexamer (state 2) in which the key SNARE assembly-activating site of Munc13 is autoinhibited by its neighbor. We propose that each Munc13 in the lateral hexamer ultimately assembles a single SNAREpin, explaining how only and exactly six SNARE complexes are templated. We suggest that state 1 and state 2 may represent two successive states in the synaptic vesicle supply chain leading to "primed" ready-release vesicles in which SNAREpins are clamped and ready to release (state 3). |
External links | Proc Natl Acad Sci U S A / PubMed:35135883 / PubMed Central |
Methods | EM (subtomogram averaging) |
Resolution | 10.0 Å |
Structure data | EMDB-25737: Subtomogram average of the hexagonal assembly in Munc13-1 C1-C2B-MUN-C2C 2D crystal between lipid bilayers EMDB-25738: Subtomogram average of Munc13-1 C1-C2B-MUN-C2C trimer within 2D crystal between lipid bilayers. EMDB-25739: Composite map of Lateral Munc13-1 C1-C2B-MUN-C2C molecule EMDB-25740: Composite map of Upright Munc13-1 C1-C2B-MUN-C2C molecule spanning two lipid bilayers EMDB-25741: A composite 3D map of Munc13-1 C1-C2B-MUN-C2C 2D crystal between lipid bilayers. |
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Keywords | EXOCYTOSIS / Synaptic Transmission / Munc13 / Membrane Fusion |