Mammalian uncoordinated-13 homolog 1 (Munc13-1) (Munc13-1)

Mammalian uncoordinated-13 homolog 1 (Munc13-1) is a large presynaptic scaffolding protein that is essential for the priming of synaptic vesicles, a process that renders them fusion-competent and ready for calcium-triggered release. The C1 domain of Munc13-1 is a specific regulatory module that binds to the secondary messenger diacylglycerol (DAG) and its pharmacological mimics, such as phorbol esters and bryostatins (Basu et al., 1998, Biochem. J.). This binding triggers the translocation of Munc13-1 to the presynaptic plasma membrane, where it facilitates the assembly of the SNARE complex by opening Syntaxin-1. Genetic variations in the UNC13A gene, which encodes Munc13-1, are strongly associated with the risk and progression of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), particularly through mechanisms involving TDP-43-mediated cryptic splicing (Brown & Al-Chalabi, 2017, Amyotroph. Lateral Scler. Frontotemporal Degener.; Ma et al., 2022, Nature). Pharmacologically, the C1 domain is a target for small molecules like bryostatin-1, which are being explored for their ability to modulate synaptic strength and cognitive function in neurodegenerative conditions. However, a major challenge in targeting this domain is achieving selectivity, as C1 domains are also present in other signaling proteins like Protein Kinase C (PKC), leading to potential off-target effects (Ruan et al., 2018, J. Med. Chem.).

Other names

UNC13AProtein unc-13 homolog AMunc13-1 C1 domainUnc-13 homolog A

Binding of diacylglycerol (DAG) or synthetic ligands to the C1 domain induces membrane translocation and activation of Munc13-1, which promotes the transition of Syntaxin-1 from a closed to an open state, thereby facilitating SNARE complex assembly and synaptic vesicle priming (Betz et al., 1998, Cell; Basu et al., 1998, Biochem. J.).