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      Dynamic Binding Mode of a Synaptotagmin-1-SNARE Complex in Solution

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          SUMMARY

          Rapid neurotransmitter release depends on the Ca 2+-sensor Synaptotagmin-1 and the SNARE complex formed by synaptobrevin, syntaxin-1 and SNAP-25. How Synaptotagmin-1 triggers release remains unclear, in part because elucidating high-resolution structures of Synaptotagmin-1-SNARE complexes has been challenging. An NMR approach based on lanthanide-induced pseudocontact shifts now reveals a dynamic binding mode where basic residues in the concave side of the Synaptotagmin-1 C 2B 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 Synaptotagmin-1 that markedly impair SNARE-complex binding in vitro and Synaptotagmin-1 function in neurons. Mutations with milder effects on binding have correspondingly milder effects on Synaptotagmin-1 function. Our results support a model whereby their dynamic interaction facilitates cooperation between synaptotagmin-1 and the SNAREs in inducing membrane fusion.

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          Interactions between macromolecules and ions: The Hofmeister series.

          Yanjie Zhang, Paul S. Cremer (2006)
          The Hofmeister series, first noted in 1888, ranks the relative influence of ions on the physical behavior of a wide variety of aqueous processes ranging from colloidal assembly to protein folding. Originally, it was thought that an ion's influence on macromolecular properties was caused at least in part by 'making' or 'breaking' bulk water structure. Recent time-resolved and thermodynamic studies of water molecules in salt solutions, however, demonstrate that bulk water structure is not central to the Hofmeister effect. Instead, models are being developed that depend upon direct ion-macromolecule interactions as well as interactions with water molecules in the first hydration shell of the macromolecule.
          Article 0 comments Cited 295 times – based on 0 reviews     Review now
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            The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices--guilty as charged?

            Thomas C. Südhof, Josep Rizo (2011)
            Neurotransmitter release is governed by proteins that have homo-logs in most types of intracellular membrane fusion, including the Sec1/Munc18 protein Munc18-1 and the SNARE proteins syntaxin-1, synaptobrevin/VAMP, and SNAP-25. The SNAREs initiate fusion by forming tight SNARE complexes that bring the vesicle and plasma membranes together. SNARE maintenance in a functional state depends on two chaperone systems (Hsc70/αCSP/SGT and synuclein); defects in these systems lead to neurodegeneration. Munc18-1 binds to an autoinhibitory closed conformation of syntaxin-1, gating formation of SNARE complexes, and also binds to SNARE complexes, which likely underlies the crucial function of Munc18-1 in membrane fusion by an as-yet unclear mechanism. Syntaxin-1 opening is mediated by Munc13s through their MUN domain, which is homologous to diverse tethering factors and may also have a general role in fusion. MUN domain activity is likely modulated in diverse presynaptic plasticity processes that depend on Ca(2+) and RIM proteins, among others.
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              Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release.

              Yibin Xu, Josep Rizo, L. Su … (2013)
              Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca(2+) sensor synaptotagmin-1, and the soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) syntaxin-1, synaptobrevin, and SNAP-25. In vitro reconstitutions have shown that syntaxin-1-SNAP-25 liposomes fuse efficiently with synaptobrevin liposomes in the presence of synaptotagmin-1-Ca(2+), but neurotransmitter release also requires Munc18-1 and Munc13 in vivo. We found that Munc18-1 could displace SNAP-25 from syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with synaptobrevin liposomes required Munc13, in addition to SNAP-25 and synaptotagmin-1-Ca(2+). Moreover, when starting with syntaxin-1-SNAP-25 liposomes, NSF-α-SNAP disassembled the syntaxin-1-SNAP-25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. We propose that fusion does not proceed through syntaxin-1-SNAP-25 heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Journal ID (iso-abbrev): Nat. Struct. Mol. Biol.
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 5 May 2015
                Publication date (Electronic): 01 June 2015
                Publication date (Print): July 2015
                Publication date PMC-release: 01 January 2016
                Volume: 22
                Issue: 7
                Pages: 555-564
                Affiliations
                [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 Molecular and Cellular Physiology, Stanford University Medical School, Stanford, California, USA
                [5 ]Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California, USA
                [6 ]Institute for Research in Biomedicine, Bellinzona, Switzerland
                [7 ]Department of Chemistry, University of Cambridge, Cambridge, UK
                [8 ]Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
                [9 ]Department of Chemistry and Center for Drug Discovery and Design, Southern Methodist University, Dallas, Texas, USA
                [10 ]Department of Chemistry, University of Basel, Basel, Switzerland
                [11 ]Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, The Netherlands
                Author notes
                Correspondence should be addressed to J.R. ( jose@ 123456arnie.swmed.edu )
                Article
                Manuscript ID: NIHMS685377
                DOI: 10.1038/nsmb.3035
                PMC ID: 4496268
                PubMed ID: 26030874
                SO-VID: 49bc06b7-739c-43fa-8ce6-296558f48fa8
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                ScienceOpen disciplines: Molecular biology

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