Ca2+ signalling in neurons through calmodulin (CaM) has a prominent function in regulating synaptic vesicle trafficking, transport, and fusion. Importantly, Ca2+-CaM binds a conserved region in the priming proteins Munc13-1 and ubMunc13-2 and thus regulates synaptic neurotransmitter release in neurons in response to residual Ca2+signals. We solved the structure of Ca2+ 4-CaM in complex with the CaM-binding domain of Munc13-1, which features a novel 1-5-8-26 CaM-binding motif with two separated mobile structural modules, each involving a CaM domain. Photoaffinity labelling data reveal the same modular architecture in the complex with the ubMunc13-2 isoform. The N-module can be dissociated with EGTA to form the half-loaded Munc13/Ca2+2-CaM complex. The Ca 2 regulation of these Munc13 isoforms can therefore be explained by the modular nature of the Munc13/Ca 2+-CaM interactions, where the C-module provides a high-affinity interaction activated at nanomolar [Ca2+] i, whereas the N-module acts as a sensor at micromolar [Ca2+] i. This Ca2+/CaM- binding mode of Munc13 likely constitutes a key molecular correlate of the characteristic Ca2+-dependent modulation of short-term synaptic plasticity.
- Neurotransmitter release
- Short-term plasticity