Figure 5: The CT and AH motif combine to localize and gate complexin function on SVs.

The CT motif, spanning residues 128–143 binds membranes in an unstructured conformation through insertion of hydrophobic phenylalanine residues at small packing defects. An increased density of such packing defects on highly curved membranes confers an increased affinity for highly curved SVs. The AH motif, spanning residues 110–124, also binds membranes in an initially unstructured conformation through insertion of hydrophobic side chains. In the presence of larger packing defects, found only on highly curved membranes, the AH motif can convert into a helical structure. The inhibitory function of complexin is only activated (red/orange star) upon helix formation by the AH motif. When the AH motif is unstructured, complexin’s inhibitory function is inactivated (empty stars). Complexin thus employs rheostat-like binding by the CT motif to preferentially localize the protein to SVs combined with a binary switch-like helical folding transition of the AH motif to gate its inhibitory function only at the SV surface.