The Role of the C2C Protein Domain in the Synaptic Hub Protein UNC-13

Overview

The synaptic hub protein Munc13 plays a pivotal role in almost all known forms of fast chemical synaptic transmission. This essential protein has also been shown to mediate several forms of use-dependent plasticity, but the mechanisms it uses to mediate synaptic vesicle fusion and plasticity are not well understood. Munc13 is a large protein that comprises several domains. However almost nothing is currently known about its C-terminal C2 domain (C2C). We used the model organism C. elegans to explore the C2C domain of the worm ortholog UNC-13. In particular, the effects of several C2C mutations introduced via CRISPR Cas9 genome editing on nervous system function were assessed using two quantitative behavioral assays (Aldicarb and Locomotion assays). The Aldicarb and Locomotion results show that animals with an early stop before C2C and ΔC2C/ΔCTD animals take longer to paralyze and move slower on average than wild type worms, consistent with a defect in synaptic transmission. Additionally, mouse C2C functionally replaced worm C2C by both assays, indicating a deep evolutionary conservation of its domain function at the synapse. These results suggest that mutations in UNC-13 C2C severely inhibit neurotransmitter exocytosis, revealing the vital role C2C plays in nervous system function. Separate studies from our lab discovered a strong membrane-binding property of the C2C domain, so disruptions in C2C may impair a critical interaction of UNC-13 with either the plasma membrane or synaptic vesicles. We propose that the C2C domain binds to synaptic vesicles to promote fusion, but further studies on the biochemical and functional properties of C2C will be required.

Competition history

• AJAS 2019 Category not listed

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