title: Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution.
abstract: Rapid neurotransmitter release depends on the Ca2+ sensor Synaptotagmin-1 (Syt1) and the SNARE complex formed by synaptobrevin, syntaxin-1 and SNAP-25. How Syt1 triggers release has been unclear, partly because elucidating high-resolution structures of Syt1-SNARE complexes has been challenging. An NMR approach based on lanthanide-induced pseudocontact shifts now reveals a dynamic binding mode in which basic residues in the concave side of the Syt1 C2B-domain β-sandwich interact with a polyacidic region of the SNARE complex formed by syntaxin-1 and SNAP-25. The physiological relevance of this dynamic structural model is supported by mutations in basic residues of Syt1 that markedly impair SNARE-complex binding in vitro and Syt1 function in neurons. Mutations with milder effects on binding have correspondingly milder effects on Syt1 function. Our results support a model whereby dynamic interaction facilitates cooperation between Syt1 and the SNAREs in inducing membrane fusion.
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Brewer
authors.affiliation: 1] Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, California, USA. [2] Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California, USA.
authors.forename: Taulant
authors.initials: T
authors.lastname: Bacaj
authors.affiliation: 1] Institute for Research in Biomedicine, Bellinzona, Switzerland. [2] Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Carlo
authors.identifier: 0000000299238590
authors.initials: C
authors.lastname: Camilloni
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Swarbrick
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [4] Department of Chemistry, Southern Methodist University, Dallas, Texas, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Zhou
authors.affiliation: 1] Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, California, USA. [2] Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barlow
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xu
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Alpay B
authors.initials: AB
authors.lastname: Seven
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Prinslow
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Voleti
authors.affiliation: Department of Chemistry, University of Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Alexandre M J J
authors.initials: AM
authors.lastname: Bonvin
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.affiliation: 1] Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, California, USA. [2] Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.affiliation: 1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D050600:SNARE Proteins / Q000737:chemistry / Q000378:metabolism*; D050863:Synaptotagmin I / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050600:SNARE Proteins; D050863:Synaptotagmin I