Membrane curvature sensing by the C-terminal domain of complexin

Complexin functions at presynaptic nerve terminals to inhibit spontaneous SNARE-mediated synaptic vesicle (SV) exocytosis, while enhancing stimulated neurotransmitter release. The C-terminal domain (CTD) of complexin is essential for its inhibitory function and has been implicated in localizing complexin to SVs via direct membrane interactions. Here we show that complexin’s CTD is highly sensitive to membrane curvature, which it senses via tandem motifs, a C-terminal motif containing a mix of bulky hydrophobic and positively charged residues, and an adjacent amphipathic region that can bind membranes in either a disordered or a helical conformation. Helix formation requires membrane packing defects found on highly curved membrane surfaces. Mutations that disrupt helix formation without disrupting membrane binding compromise complexin’s inhibitory function in vivo. Thus, this membrane curvature-dependent conformational transition, combined with curvature-sensitive binding by the adjacent C-terminal motif, constitute a novel mechanism for activating complexin’s inhibitory function on the surface of SVs.