Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch.
Synaptotagmin I is a synaptic vesicle protein that is thought to act as a Ca2+ sensor in neurotransmitter release. The first C2 domain of synaptotagmin I (C2A domain) contains a bipartite Ca2+-binding motif and interacts in a Ca2+-dependent manner with syntaxin, a central component of the membrane fusion complex. Analysis by nuclear magnetic resonance spectroscopy and site-directed mutagenesis shows that this interaction is mediated by the cooperative action of basic residues surrounding the Ca2+-binding sites of the C2A domain and is driven by a change in the electrostatic potential of the C2A domain induced by Ca2+ binding. A model is proposed whereby synaptotagmin acts as an electrostatic switch in Ca2+-triggered synaptic vesicle exocytosis, promoting a structural rearrangement in the fusion machinery that is effected by its interaction with syntaxin.
Shao
X
X
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas 75235, USA.
Li
C
C
Fernandez
I
I
Zhang
X
X
Südhof
T C
TC
Rizo
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002942:Circular Dichroism; D005982:Glutathione Transferase; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D017354:Point Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D050765:Qa-SNARE Proteins; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D050863:Synaptotagmin I; D050857:Synaptotagmins; D013816:Thermodynamics
D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050765:Qa-SNARE Proteins; D011993:Recombinant Fusion Proteins; D050863:Synaptotagmin I; D050857:Synaptotagmins; D005982:Glutathione Transferase; D002118:Calcium