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=== ''SNARE domain'' ===
=== ''SNARE domain'' ===


The SNARE domain is approximately 60-70 residues long and is located immediately adjacent to a C-terminal transmembrane anchor. It contains a repeating heptad pattern of hydrophobic residues. Their orientation places them in an alpha-helical structure so that all the hydrophobic side chains are located on the same face of the helix<ref> PMID: 11786915 </ref><ref> PMID: 9731768 </ref> Sutton et al. 1998). SNARE domains allow the four SNAREs protein to assemble into parallel four-helix bundles. This parallel arrangement brings the transmembrane anchors and the membranes closer (Hanson et al. 1997).
The SNARE domain is approximately 60-70 residues long and is located immediately adjacent to a C-terminal transmembrane anchor. It contains a repeating heptad pattern of hydrophobic residues. Their orientation places them in an alpha-helical structure so that all the hydrophobic side chains are located on the same face of the helix.<ref> PMID: 11786915 </ref><ref> PMID: 9731768 </ref><ref> PMID: 9759724 </ref> SNARE domains allow the four SNAREs protein to assemble into parallel four-helix bundles. This parallel arrangement brings the transmembrane anchors and the membranes closer. <ref> PMID: 9267032 </ref>


=== ''Structure of individual layers'' ===
=== '' “0”-layers'' ===


The centre of the four-helix bundle is constituted of 16 layers. These layers are composed of hydrophobic side chains, which are perpendicular to the axis of the four-helix bundle, except for the central “0”-layer. This last one consists of three glutamine (Q) and one arginine (R) highly conserved residues. Glutamine residues are found in syntaxin and both SNAP-25 and arginine residues in synaptobrevin. Those highly conserved residues have led to a new classification of SNAREs into Q- and R-SNAREs.  
The centre of the four-helix bundle is constituted of 16 layers. These layers are composed of hydrophobic side chains, which are perpendicular to the axis of the four-helix bundle, except for the central “0”-layer. This last one consists of three glutamine (Q) and one arginine (R) highly conserved residues. Glutamine residues are found in syntaxin and both SNAP-25 and arginine residues in synaptobrevin. Those highly conserved residues have led to a new classification of SNAREs into Q- and R-SNAREs. <ref> PMID: 9861047 </ref> Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs.<ref> PMID: 11237004 </ref><ref> PMID: 11001046 </ref> In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane.


=== ''Surface interactions'' ===
=== ''Surface interactions'' ===
Line 34: Line 34:


== '''Regulation''' ==
== '''Regulation''' ==
In addition to SNARE motifs and membrane anchors, SNARE proteins have autonomously folding N-terminal domains. These autonomously folded domains are able to regulate SNARE assembly. Synthaxin 7 has a three-helix-bundle domain, which with the profiling-like domain Ykt6p of yeast can lightly inhibit the SNARE assembly. Sso1p is the yeast ortholog of syntaxin. Sso1p can bind to the SNARE motif. This binding generates a closed conformation that strongly inhibits the entry of Sso1p into SNARE complexes. The main role of these autonomously folded domains is still under research. However, one of the known function is the recruitment of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs. <ref>doi:  10.1146/mbc.E09-03-0203</ref>
In addition to SNARE motifs and membrane anchors, SNARE proteins have autonomously folding N-terminal domains. These autonomously folded domains are able to regulate SNARE assembly. Synthaxin 7 has a three-helix-bundle domain, which with the profiling-like domain Ykt6p of yeast can lightly inhibit the SNARE assembly.<ref> PMID: 11474112 </ref> Sso1p is the yeast ortholog of syntaxin. Sso1p can bind to the SNARE motif. This binding generates a closed conformation that strongly inhibits the entry of Sso1p into SNARE complexes.<ref> PMID: 10048921 </ref><ref> PMID: 11017200 </ref><ref> PMID: 11777922 </ref><ref> PMID: 9731774 </ref> The main role of these autonomously folded domains is still under research. However, one of the known functions is the recruitment of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs.<ref>doi:  10.1146/mbc.E09-03-0203</ref>
 
== ''' Effects of toxins on SNAREs ''' ==
 
Many neuroxines affect SNARE proteins. Botulinum and Tetanus toxines prevent vesicle recycling by targeting the SNAREs, thus resulting in poor muscle control, spasms, paralysis and even death.
The Botulinum toxin attacks the SNAP-25 protein of the SNARE complex by cleaving the SNAP-25 protein, thus preventing synaptic vesicle from fusing with the cellular synaptic membrane and releasing their neurotransmitters.<ref> PMID: 17666428 </ref> Regarding the Tetanus toxin, it attacks the protein synaptobrevin on the synaptic vesicle.<ref> PMID: 7588600 </ref>
These toxins result in Tetanus, a prolonged contraction of skeletal muscle fibres and Botulism, a type of food poisoning that can also lead to muscle paralysis and even to death.


== '''2NPS in cancers/diseases''' ==




Revision as of 13:40, 22 December 2013

PDB ID 2nps

Drag the structure with the mouse to rotate
2nps, resolution 2.50Å ()
Gene: Vamp4_predicted (Mus musculus), syntaxin 13 (Rattus norvegicus), Vti1a (Rattus norvegicus), STX6 (Homo sapiens)
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml





IntroductionIntroduction

Important biological processes, such as synaptic transmission and cellular trafficking in Eukaryotes require SNARE proteins that are thought to play a crucial role in membrane fusion.[1][2][3][4] To connect membranes and allow their fusion, SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) proteins assemble into a core-complex of four parallel helices[5], , Sutton et al. 1998). The SNARE complex assembly is mediated by a conserved SNARE motif consisting of 60-70 amino acids (Weimbs et al. 1997). The best-studied SNAREs are the neuronal and the endosomal SNARE complexes. The Neuronal SNARE complex mediates exocytosis of synaptic vesicles in the neurons and includes the vesicle protein synaptobrevin (also called VAMP), the membrane proteins SNAP-25 and syntaxin 1 (Sutton et al. 1998). The Endosomal SNARE complex includes syntaxin7, syntaxin8, vti1b and andobrevin (also referred as VAMP-8) and is responsible for the fusion of late endosomes/lysosomes (Advani et al., 1999; Prekeris et al., 1999; Ward et al., 2000; Antonin et al., 2000; Mullock et al., 2000; Nakamura et al., 2000). Moreover, SNAREs can be divided into two categories: the v-(vesicle) SNAREs, which are found in the vesicle membrane and the t-(target) SNAREs, which are anchored in the target membrane (Söllner et al. 1993b).

Membrane fusion mechanismMembrane fusion mechanism

Membrane Fusion requires the assembly of the core complex. Free t-SNAREs that are organized in clusters first assemble into acceptor complexes thanks to SM (Sec1/Munc18-related) proteins. Acceptor complexes can then interact with the v-SNAREs through the N-terminal domain of the SNARE motif. This enables the formation of four-helical trans-complexes, in which only the N-terminal portions of the SNARE motifs are bound. This binding evolves from a loose to a tight state, thus leading to the formation of a fusion pore. During the fusion, the conformation relaxes to a cis-configuration. Cis-complexes dissociate thanks to proteins and cofactors. T- and v-SNAREs can be separated and recycled.[6][7]


StructureStructure

SNARE domainSNARE domain

The SNARE domain is approximately 60-70 residues long and is located immediately adjacent to a C-terminal transmembrane anchor. It contains a repeating heptad pattern of hydrophobic residues. Their orientation places them in an alpha-helical structure so that all the hydrophobic side chains are located on the same face of the helix.[8][9][10] SNARE domains allow the four SNAREs protein to assemble into parallel four-helix bundles. This parallel arrangement brings the transmembrane anchors and the membranes closer. [11]

“0”-layers“0”-layers

The centre of the four-helix bundle is constituted of 16 layers. These layers are composed of hydrophobic side chains, which are perpendicular to the axis of the four-helix bundle, except for the central “0”-layer. This last one consists of three glutamine (Q) and one arginine (R) highly conserved residues. Glutamine residues are found in syntaxin and both SNAP-25 and arginine residues in synaptobrevin. Those highly conserved residues have led to a new classification of SNAREs into Q- and R-SNAREs. [12] Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs.[13][14] In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane.

Surface interactionsSurface interactions

Polar and ionic surface interactions help stabilisation of the helix bundle. These include six pairs of opposed charges that are conserved between SNAREs families. For instance, Glu 179 in syntaxin 7 forms a salt bridge with Arg 148 in vti1b. Another example of a conserved interaction is a salt bridge between Arg 32 of endobrevin and Asp 177 of syntaxin 8. In the neuronal complex, the corresponding residues are Lys 52 in synaptobrevin 2 and Asp 172 in SNAP-25. A positively charged amino acid in this position (mostly Lys) is found in all synaptobrevins, except for members of the VAMP7-subfamily, but is missing from the ykt6- (Ser/Asn/Ala) and sec22-subfamilies (Asp/Glu). Most d-helices contain a negatively charged residue at this position.A third example is Glu 207 of syntaxin 7, which forms a salt bridge with Arg 176 in vti1b. Again, this interaction is conserved: most syntaxins contain an Asp or Glu at this position, which is matched by an Arg or Lys (occasionally also Asn) in the c-helix SNARE motifs (except for members of the membrin and gs28/Gos1-subfamilies).[15]


RegulationRegulation

In addition to SNARE motifs and membrane anchors, SNARE proteins have autonomously folding N-terminal domains. These autonomously folded domains are able to regulate SNARE assembly. Synthaxin 7 has a three-helix-bundle domain, which with the profiling-like domain Ykt6p of yeast can lightly inhibit the SNARE assembly.[16] Sso1p is the yeast ortholog of syntaxin. Sso1p can bind to the SNARE motif. This binding generates a closed conformation that strongly inhibits the entry of Sso1p into SNARE complexes.[17][18][19][20] The main role of these autonomously folded domains is still under research. However, one of the known functions is the recruitment of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs.[21]

Effects of toxins on SNAREs Effects of toxins on SNAREs

Many neuroxines affect SNARE proteins. Botulinum and Tetanus toxines prevent vesicle recycling by targeting the SNAREs, thus resulting in poor muscle control, spasms, paralysis and even death. The Botulinum toxin attacks the SNAP-25 protein of the SNARE complex by cleaving the SNAP-25 protein, thus preventing synaptic vesicle from fusing with the cellular synaptic membrane and releasing their neurotransmitters.[22] Regarding the Tetanus toxin, it attacks the protein synaptobrevin on the synaptic vesicle.[23] These toxins result in Tetanus, a prolonged contraction of skeletal muscle fibres and Botulism, a type of food poisoning that can also lead to muscle paralysis and even to death.


External ressourcesExternal ressources

ReferencesReferences

A l'endroit de ton petit numéro [24] ou si c'est un doi [25] et à la fin de l'article


  1. ↑ Brunger AT. Structure of proteins involved in synaptic vesicle fusion in neurons. Annu Rev Biophys Biomol Struct. 2001;30:157-71. PMID:11340056 doi:http://dx.doi.org/10.1146/annurev.biophys.30.1.157
  2. ↑ Chen YA, Scheller RH. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol. 2001 Feb;2(2):98-106. PMID:11252968 doi:http://dx.doi.org/10.1038/35052017
  3. ↑ Jahn R, Lang T, Sudhof TC. Membrane fusion. Cell. 2003 Feb 21;112(4):519-33. PMID:12600315
  4. ↑ Rizo J, Sudhof TC. Snares and Munc18 in synaptic vesicle fusion. Nat Rev Neurosci. 2002 Aug;3(8):641-53. PMID:12154365 doi:http://dx.doi.org/10.1038/nrn898
  5. ↑ Antonin W, Fasshauer D, Becker S, Jahn R, Schneider TR. Crystal structure of the endosomal SNARE complex reveals common structural principles of all SNAREs. Nat Struct Biol. 2002 Feb;9(2):107-11. PMID:11786915 doi:http://dx.doi.org/10.1038/nsb746
  6. ↑ Jahn R, Scheller RH. SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43. Epub 2006 Aug 16. PMID:16912714 doi:http://dx.doi.org/10.1038/nrm2002
  7. ↑ Jahn R, Scheller RH. SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43. Epub 2006 Aug 16. PMID:16912714 doi:http://dx.doi.org/10.1038/nrm2002
  8. ↑ Antonin W, Fasshauer D, Becker S, Jahn R, Schneider TR. Crystal structure of the endosomal SNARE complex reveals common structural principles of all SNAREs. Nat Struct Biol. 2002 Feb;9(2):107-11. PMID:11786915 doi:http://dx.doi.org/10.1038/nsb746
  9. ↑ Poirier MA, Xiao W, Macosko JC, Chan C, Shin YK, Bennett MK. The synaptic SNARE complex is a parallel four-stranded helical bundle. Nat Struct Biol. 1998 Sep;5(9):765-9. PMID:9731768 doi:10.1038/1799
  10. ↑ Sutton RB, Fasshauer D, Jahn R, Brunger AT. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature. 1998 Sep 24;395(6700):347-53. PMID:9759724 doi:http://dx.doi.org/10.1038/26412
  11. ↑ Hanson PI, Roth R, Morisaki H, Jahn R, Heuser JE. Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy. Cell. 1997 Aug 8;90(3):523-35. PMID:9267032
  12. ↑ Fasshauer D, Sutton RB, Brunger AT, Jahn R. Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15781-6. PMID:9861047
  13. ↑ Bock JB, Matern HT, Peden AA, Scheller RH. A genomic perspective on membrane compartment organization. Nature. 2001 Feb 15;409(6822):839-41. PMID:11237004 doi:http://dx.doi.org/10.1038/35057024
  14. ↑ McNew JA, Parlati F, Fukuda R, Johnston RJ, Paz K, Paumet F, Sollner TH, Rothman JE. Compartmental specificity of cellular membrane fusion encoded in SNARE proteins. Nature. 2000 Sep 14;407(6801):153-9. PMID:11001046 doi:http://dx.doi.org/10.1038/35025000
  15. ↑ doi: 10.1038/mbc.E09-03-0203
  16. ↑ Tochio H, Tsui MM, Banfield DK, Zhang M. An autoinhibitory mechanism for nonsyntaxin SNARE proteins revealed by the structure of Ykt6p. Science. 2001 Jul 27;293(5530):698-702. PMID:11474112 doi:10.1126/science.1062950
  17. ↑ Fiebig KM, Rice LM, Pollock E, Brunger AT. Folding intermediates of SNARE complex assembly. Nat Struct Biol. 1999 Feb;6(2):117-23. PMID:10048921 doi:10.1038/5803
  18. ↑ Munson M, Chen X, Cocina AE, Schultz SM, Hughson FM. Interactions within the yeast t-SNARE Sso1p that control SNARE complex assembly. Nat Struct Biol. 2000 Oct;7(10):894-902. PMID:11017200 doi:10.1038/79659
  19. ↑ Munson M, Hughson FM. Conformational regulation of SNARE assembly and disassembly in vivo. J Biol Chem. 2002 Mar 15;277(11):9375-81. Epub 2002 Jan 2. PMID:11777922 doi:http://dx.doi.org/10.1074/jbc.M111729200
  20. ↑ Nicholson KL, Munson M, Miller RB, Filip TJ, Fairman R, Hughson FM. Regulation of SNARE complex assembly by an N-terminal domain of the t-SNARE Sso1p. Nat Struct Biol. 1998 Sep;5(9):793-802. PMID:9731774 doi:http://dx.doi.org/10.1038/1834
  21. ↑ doi: 10.1146/mbc.E09-03-0203
  22. ↑ Meng J, Wang J, Lawrence G, Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci. 2007 Aug 15;120(Pt 16):2864-74. Epub 2007 Jul 31. PMID:17666428 doi:http://dx.doi.org/10.1242/jcs.012211
  23. ↑ Pellegrini LL, O'Connor V, Lottspeich F, Betz H. Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion. EMBO J. 1995 Oct 2;14(19):4705-13. PMID:7588600
  24. ↑ Jahn R, Scheller RH. SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43. Epub 2006 Aug 16. PMID:16912714 doi:http://dx.doi.org/10.1038/nrm2002
  25. ↑ Wescott MP, Rovira M, Reichert M, von Burstin J, Means A, Leach SD, Rustgi AK. Pancreatic ductal morphogenesis and the Pdx1 homeodomain transcription factor. Mol Biol Cell. 2009 Nov;20(22):4838-44. doi: 10.1091/mbc.E09-03-0203. Epub 2009, Sep 30. PMID:19793922 doi:http://dx.doi.org/10.1091/mbc.E09-03-0203

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