Biophysical Society Conference | Estes Park 2023

Membrane Budding and Fusion

Tuesday Speaker Abstracts

MOLECULAR INSIGHTS INTO MUNC13 AND COMPLEXIN FUNCTION AT THE SYNAPSE

Jeremy Dittman ; 1 Weill Cornell Medicine, Biochemistry, New York, NY, USA

Chemical synaptic transmission requires a tightly choreographed sequence of molecular events, and two major SNARE-assembly regulators in the presynaptic terminal are Munc13 and Complexin (Cpx). Loss of the C. elegans Cpx ortholog, CPX-1, results in elevated spontaneous synaptic vesicle (SV) fusion as well as loss of calcium-triggered fusion. We previously demonstrated that the C-terminus of CPX-1 is required for proper localization to SVs, and we now show that this domain can be fully replaced by unrelated SV-targeting motifs to restore CPX-1 functionality. We identified a critical domain at the C-terminus of C. elegans UNC-13 in a forward genetic suppressor screen of the cpx-1 null mutant and found that this domain is required at an early stage in SV docking. Biochemical and structure/function assays further dissected this region of UNC-13 to identify conserved membrane- and protein-binding modules within the C-terminus of UNC-13. Taken together with work from our lab and others on Munc13, we propose a modular functional architecture within Munc13 that parallels its sequential functions during SV docking, priming, and fusion.

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