A unique C2 domain at the C terminus of Munc13 promotes synaptic vesicle priming

Abstract

Significance Rapid communication between neurons relies on the precise coordination of several presynaptic active-zone proteins. Munc13/UNC-13 is the centerpiece of this deeply conserved process, and several domains of this large cytoplasmic protein serve specific roles such as coordinating SNARE protein assembly, integrating calcium and lipid signals, and bringing synaptic vesicles close to the plasma membrane, although a mechanistic understanding of these critical steps is lacking. Here, we describe for the first time a novel C2 domain (HC2M) at the C terminus of UNC-13 that helps to bind synaptic vesicles to the plasma membrane in preparation for fusion. We demonstrate the impact of HC2M loss on nervous system function and characterize its structural, biochemical, and evolutionarily conserved features.