title: Membrane curvature sensing by the C-terminal domain of complexin.
abstract: 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.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Snead
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Rachel T
authors.initials: RT
authors.lastname: Wragg
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Dittman
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans; D002462:Cell Membrane / Q000378:metabolism*; D002942:Circular Dichroism; D005089:Exocytosis; D017353:Gene Deletion; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050600:SNARE Proteins / Q000737:chemistry; D013569:Synapses / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008055:Lipids; D008081:Liposomes; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; C095992:complexin I