The Core Complex of the Ca²⁺-Triggered Presynaptic Fusion Machinery

Synaptic neurotransmitter release is mediated by an orchestra of presynaptic proteins that precisely control and trigger fusion between synaptic vesicles and the neuron terminal at the active zone upon the arrival of an action potential. Critical to this process are the neuronal SNAREs (Soluble N-ethylmaleimide sensitive factor Attachment protein REceptor), the Ca²⁺-sensor synaptotagmin, the activator/regulator complexin, and other factors. Here, we review the interactions between the SNARE complex and synaptotagmin, with focus on the so-called primary interface between synaptotagmin and the SNARE complex that has been validated in terms of its physiological relevance. We discuss several other but less validated interfaces as well, including the so-called tripartite interface, and we discuss the pros and cons for these possible alternative interfaces. We also present new molecular dynamics simulations of the tripartite interface and new data of an inhibitor of the primary interface in a reconstituted system of synaptic vesicle fusion.