What does this research mean for the field?

Cognate and non-cognate SNARE complexes share very similar biophysical properties, assembly, and disassembly characteristics, demonstrating that the specificity of intracellular membrane fusion is not driven by the intrinsic pairing specificity of SNARE proteins. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

May 1, 1999Open Access

Mixed and Non-cognate SNARE Complexes

Key Points

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Abstract

Assembly of solubleN-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins between two opposing membranes is thought to be the key event that initiates membrane fusion. Many new SNARE proteins have recently been localized to distinct intracellular compartments, supporting the view that sets of specific SNAREs are specialized for distinct trafficking steps. We have now investigated whether other SNAREs can form complexes with components of the synaptic SNARE complex including synaptobrevin/VAMP 2, SNAP-25, and syntaxin 1. When the Q-SNAREs syntaxin 2, 3, and 4, and the R-SNARE endobrevin/VAMP 8 were used in various combinations, heat-resistant complexes were formed. Limited proteolysis revealed that these complexes contained a protease-resistant core similar to that of the synaptic complex. All complexes were disassembled by the ATPaseN-ethylmaleimide-sensitive fusion protein and its cofactor α-SNAP. Circular dichroism spectroscopy showed that major conformational changes occur during assembly, which are associated with induction of structure from unstructured monomers. Furthermore, no preference for synaptobrevin was observed during the assembly of the synaptic complex when endobrevin/VAMP 8 was present in equal concentrations. We conclude that cognate and non-cognate SNARE complexes are very similar with respect to biophysical properties, assembly, and disassembly, suggesting that specificity of membrane fusion in intracellular membrane traffic is not due to intrinsic specificity of SNARE pairing. Assembly of solubleN-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins between two opposing membranes is thought to be the key event that initiates membrane fusion. Many new SNARE proteins have recently been localized to distinct intracellular compartments, supporting the view that sets of specific SNAREs are specialized for distinct trafficking steps. We have now investigated whether other SNAREs can form complexes with components of the synaptic SNARE complex including synaptobrevin/VAMP 2, SNAP-25, and syntaxin 1. When the Q-SNAREs syntaxin 2, 3, and 4, and the R-SNARE endobrevin/VAMP 8 were used in various combinations, heat-resistant complexes were formed. Limited proteolysis revealed that these complexes contained a protease-resistant core similar to that of the synaptic complex. All complexes were disassembled by the ATPaseN-ethylmaleimide-sensitive fusion protein and its cofactor α-SNAP. Circular dichroism spectroscopy showed that major conformational changes occur during assembly, which are associated with induction of structure from unstructured monomers. Furthermore, no preference for synaptobrevin was observed during the assembly of the synaptic complex when endobrevin/VAMP 8 was present in equal concentrations. We conclude that cognate and non-cognate SNARE complexes are very similar with respect to biophysical properties, assembly, and disassembly, suggesting that specificity of membrane fusion in intracellular membrane traffic is not due to intrinsic specificity of SNARE pairing. SNAREs 1The abbreviations used are: SNARE, SNAP receptor; NSF, N-ethylmaleimide-sensitive fusion protein; SNAP, soluble NSF attachment protein; SNAP-25, synaptosomal-associated protein of 25 kDa; BoNT, botulinum neurotoxin; GST, glutathioneS-transferase; CD, circular dichroism; MALLS, multi-angle laser light scattering; PMSF, phenylmethylsulfonyl fluoride; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; Tricine, N-tris(hydroxymethyl) methylglycine represent a protein superfamily that is thought to play a key role in all intracellular membrane fusion events within eukaryotes (1Rothman J.E. Nature. 1994; 372: 55-63Crossref PubMed Scopus (2011) Google Scholar, 2Südhof T.C. Nature. 1995; 375: 645-653Crossref PubMed Scopus (1770) Google Scholar, 3Hanson P.I. Heuser J.E. Jahn R. Curr. Opin. Neurobiol. 1997; 7: 310-315Crossref PubMed Scopus (334) Google Scholar, 4Hay J.C. Scheller R.H. Curr. Opin. Cell Biol. 1997; 9: 505-512Crossref PubMed Scopus (254) Google Scholar, 5Rizo J. Südhof T.C. Nat. Struct. Biol. 1998; 5: 839-842Crossref PubMed Scopus (66) Google Scholar, 6Weis W.I. Scheller R.H. Nature. 1998; 395: 328-329Crossref PubMed Scopus (43) Google Scholar). They possess a homologous domain of approximately 60 amino acids referred to as the SNARE motif (7Weimbs T. Mostov K. Seng H.L. Hofmann K. Trends Cell Biol. 1998; 8: 260-262Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). The best characterized SNAREs are those mediating exocytosis of synaptic vesicles in neurons. They include the vesicle protein synaptobrevin (also referred to as VAMP) and the membrane proteins SNAP-25 and syntaxin 1. In vitro, these proteins form a stable ternary complex that is reversibly dissociated by the soluble ATPase NSF in conjunction with soluble cofactors termed SNAPs (8Söllner T. Whiteheart S.W. Brunner M. Erdjument-Bromage H. Geromanos S. Tempst P. Rothman J.E. Nature. 1993; 362: 318-324Crossref PubMed Scopus (2637) Google Scholar, 9Söllner T. Bennett M.K. Whiteheart S.W. Scheller R.H. Rothman J.E. Cell. 1993; 75: 409-418Abstract Full Text PDF PubMed Scopus (1586) Google Scholar). Assembly and disassembly of SNAREs has recently been investigated in detail by several laboratories (5Rizo J. Südhof T.C. Nat. Struct. Biol. 1998; 5: 839-842Crossref PubMed Scopus (66) Google Scholar, 6Weis W.I. Scheller R.H. Nature. 1998; 395: 328-329Crossref PubMed Scopus (43) Google Scholar, 10Katz L. Hanson P.I. Heuser J.E. Brennwald P. EMBO J. 1998; 17: 6200-6209Crossref PubMed Scopus (80) Google Scholar, 11Ungermann C. Sato K. Wickner W. Nature. 1998; 396: 543-548Crossref PubMed Scopus (279) Google Scholar, 12Fiebig K. Rice L.M. Pollock E. Brünger A.T. Nat. Struct. Biol. 1999; 6: 117-123Crossref PubMed Scopus (237) Google Scholar). It is generally believed that it is the formation of a ternary complex between complementary SNAREs residing on the membranes destined to fuse (“trans” complexes) that drives the fusion reaction. After fusion, the complexes are disassembled by NSF and SNAPs and thus re-energized for another round of membrane fusion. According to the original SNARE hypothesis (1Rothman J.E. Nature. 1994; 372: 55-63Crossref PubMed Scopus (2011) Google Scholar), each fusion step in membrane trafficking would be mediated by a unique set of SNAREs. These would function only in one fusion step and be excluded from others. This specificity was thought to be caused by the intrinsic affinity of SNAREs for each other, i.e. only cognate SNAREs were thought to bind to each other. Recently, however, it has become clear that at least some SNAREs can function in multiple trafficking steps such as the yeast proteins Sed5p and Vti1p (13Fischer von Mollard G. Nothwehr S.F. Stevens T.H. J. Cell Biol. 1997; 137: 1511-1524Crossref PubMed Scopus (175) Google Scholar, 14Götte M. Fischer von Mollard G. Trends Cell Biol. 1998; 8: 215-218Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 15Nichols B.J. Pelham H.R. Biochim. Biophys. Acta. 1998; 1404: 9-31Crossref PubMed Scopus (127) Google Scholar). Furthermore, these proteins apparently participate in the formation of several different SNARE complexes, suggesting that they are able to pair with more than one set of partners. SNARE complex assembly is mediated by the SNARE motifs of the participating proteins which form a protease-resistant core domain (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google Scholar,17Poirier M.A. Xiao W. Macosko J.C. Chan C. Shin Y.K. Bennett M.K. Nat. Struct. Biol. 1998; 5: 765-769Crossref PubMed Scopus (419) Google Scholar). The transmembrane regions of syntaxin and synaptobrevin are directly adjacent to the SNARE motifs, aligned at one end of the core domain (18Hanson P.I. Roth R. Morisaki H. Jahn R. Heuser J.E. Cell. 1997; 90: 523-535Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, 19Lin R.C. Scheller R.H. Neuron. 1997; 19: 1087-1094Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). A dramatic increase in α-helical content is associated with SNARE complex formation, showing that major conformational changes occur during assembly. (12Fiebig K. Rice L.M. Pollock E. Brünger A.T. Nat. Struct. Biol. 1999; 6: 117-123Crossref PubMed Scopus (237) Google Scholar, 20Fasshauer D. Bruns D. Shen B. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 4582-4590Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 22Rice L.M. Brennwald P. Brünger A.T. FEBS Lett. 1997; 415: 49-55Crossref PubMed Scopus (60) Google Scholar, 23Nicholson K.L. Munson M. Miller R.B. Filip T.J. Fairman R. Hughson F.M. Nat. Struct. Biol. 1998; 5: 793-802Crossref PubMed Scopus (174) Google Scholar). These features, together with the heat stability of the complex (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar), led to the proposal that the SNAREs “zipper up” during assembly, forcing the transmembrane domains into close proximity and thus pull the fusing membranes together (3Hanson P.I. Heuser J.E. Jahn R. Curr. Opin. Neurobiol. 1997; 7: 310-315Crossref PubMed Scopus (334) Google Scholar, 4Hay J.C. Scheller R.H. Curr. Opin. Cell Biol. 1997; 9: 505-512Crossref PubMed Scopus (254) Google Scholar). The energy released during assembly would thus be used to overcome the energy barrier separating the two membranes (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). The central domain of the synaptic SNARE complex is represented by a 12-nm-long bundle consisting of four parallel α-helices that are wound around each other (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google Scholar). The interacting amino acids form distinct layers perpendicular to the axis of the four helix bundle, which are similar to those found in typical coiled-coils. These layers are formed by hydrophobic amino acid side chains with the exception of an ionic layer in the middle which consists of three glutamine residues, contributed by syntaxin and the two SNARE-motifs of SNAP-25, and one arginine residue, contributed by synaptobrevin (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google Scholar). The striking conservation of the glutamine (Q) and arginine (R) throughout the entire SNARE superfamily led us to reclassify SNAREs into Q- and R-SNAREs (25Fasshauer D. Sutton R.B. Brünger A.T. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15781-15786Crossref PubMed Scopus Google Scholar). The hydrophobic layers in the four helix bundle are at the are more The to form four helix is the of the SNAREs that is the entire superfamily (25Fasshauer D. Sutton R.B. Brünger A.T. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15781-15786Crossref PubMed Scopus Google Scholar). the of core conservation the SNARE is as specific as were observed at the of the synaptic SNARE between SNAP-25 and syntaxin (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google Scholar), which (25Fasshauer D. Sutton R.B. Brünger A.T. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15781-15786Crossref PubMed Scopus Google Scholar). It is not to which these to the stability of the SNARE complex to the of SNARE assembly. the between more of the SNARE superfamily is such to however, the of the SNARE complex not a on complex assembly and one would that complexes form not only between cognate between non-cognate SNAREs. complex formation is one for the specificity of membrane fusion In to have investigated whether different SNAREs can form complexes, and whether these complexes the SNARE complex. In have on complexes of the SNAREs. that all SNAREs investigated can be in to complexes of very similar biophysical All complexes have a α-helical a protease-resistant core are and are disassembled by Furthermore, the synaptobrevin endobrevin/VAMP is not from synaptobrevin assembly with the SNAREs SNAP-25 and syntaxin 1. NSF and in for fusion proteins were by S. Whiteheart and J. E. Rothman in the for a protein was by A. T. Brünger The protein were from for synaptobrevin and syntaxin by R. H. of and for by T. C. of light chain of botulinum was a of H. was by of the on from from and was used as a The was into and All from the three different were The amino acid was to T. G. W. Biol. Cell. 1998; 9: PubMed Scopus Google Scholar, H.R. R. Scheller R.H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). were by the a was by at for and in PMSF, at a protein of were by at for 60 After of the to a were for at with a synaptobrevin L. Hanson P.I. Jahn R. EMBO J. 1995; PubMed Scopus Google a that was in The been were to for and with The were to and D. PubMed Scopus Google Scholar). The and of the were by and the for for and the for R. K. PubMed Scopus Google Scholar). were by with for into the The for the of was into and in a fusion protein with The domains of syntaxin syntaxin and syntaxin were into the (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google and in fusion proteins a In to was into the and in an In four and were by by the of S. R. PubMed Scopus Google Scholar). in and to the SNAP-25 (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google was observed not was by affinity on as D. Bruns D. Shen B. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 4582-4590Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). After the was by proteins syntaxin (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google syntaxin syntaxin syntaxin synaptobrevin (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google were by as (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). After from the affinity all proteins were and by on an After the proteins were with a of in The were and The proteins were as by gel All and ternary complexes were a assembly of the monomers. were by at and the PubMed Scopus Google Scholar). The ternary complexes were to in in a of complex at 25 for by was by on a by multi-angle laser light the was by and the on complexes were disassembled by of NSF, in for at in the of light The was by the for at in the was in of NSF and the ATPase of NSF was by with an for disassembly, of SNAP-25 by was for of SNAP-25, the C. J. L. Fischer von Mollard G. Jahn R. J. Cell Biol. 1995; PubMed Scopus Google was were by steps of with a of on a to a with a Cell were in with of All were an at in the changes of the to complex formation, the were with the of the the are the of the are the of amino acid residues, and are the of the the at was between 25 and with a of was as by Nature. PubMed Scopus Google Scholar). When for were in 60 and at for on a polyacrylamide of the of the protease-resistant core gel was used H. von G. PubMed Scopus Google Scholar). was on a in at a of The were by at light at and and were the and of was as by P. Acta. 1993; 272: Scopus Google Scholar). each of protein and was of with respect to a in of the is for proteins J. T. PubMed Scopus Google and was set to for the of the light different SNARE proteins were for to form complexes with the SNAREs in These syntaxin 2, syntaxin 3, and syntaxin 4, three of syntaxin that a similar domain structure M.K. J.E. K. Scheller R.H. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar), and are homologous within the SNARE motifs The is not to the amino acids participating in core on the and intracellular these are in of vesicles with the membrane and thus with the SNAREs in the the R-SNARE endobrevin/VAMP a of which is localized to T. G. W. Biol. Cell. 1998; 9: PubMed Scopus Google Scholar, H.R. R. Scheller R.H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the SNARE only the amino acids of the core layers are with in the of the the all proteins were and for The proteins were in various and by for the formation of It was that the synaptic SNARE complex is to a used for complex formation T. H. S. T. Südhof T.C. H. EMBO J. 1994; PubMed Scopus Google Scholar). the SNARE combinations, formed complexes, as by the of protein with to ternary complexes complex was observed with the and syntaxin 4, complex formation was when the were by not three complexes including synaptobrevin and These complexes were by and to it was that the core domain of the synaptic SNARE i.e. the of the interacting SNARE motifs, is SNARE motifs are (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google Scholar, M.A. Xiao W. Macosko J.C. Chan C. Shin Y.K. Bennett M.K. Nat. Struct. Biol. 1998; 5: 765-769Crossref PubMed Scopus (419) Google Scholar). in of all three complexes with a at and a of between 8 and When the of the and synaptobrevin complexes were not to a was of the of the This to the for the synaptic SNARE complex (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google and that the the domain of the the represent the SNARE These that protease-resistant core domains are formed that are very similar to that of the synaptic complex. such the SNARE motifs was observed with the complex not have the of complex by that a major from the which contained a of the core complex SNARE The the domain of syntaxin was and at a to a The from the was by MALLS, a for a of the of the of the complex P. Acta. 1993; 272: Scopus Google Scholar). The in a of which is similar to that of the core of the synaptic SNARE complex (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google Scholar). A similar was when the of the synaptobrevin complex was This that these complexes the four SNARE motifs in a the synaptic complex is represented by an bundle of four α-helices a α-helical in of the three non-cognate complexes in similar not suggesting that the structure of all complexes is very spectroscopy as a to the stability of the has that the synaptic complex is to a believed to be a of SNARE complexes (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). in 3, the of the three complexes are All three complexes are as stable as the complex and more stable than the SNARE complex L.M. Brennwald P. Brünger A.T. FEBS Lett. 1997; 415: 49-55Crossref PubMed Scopus (60) Google Scholar). these that the of all complexes are very similar and that to not major in the and biophysical The between the various SNARE complexes us to whether these complexes are with respect to the of the disassembly a specialized NSF is thought to on all SNARE complexes (1Rothman J.E. Nature. 1994; 372: 55-63Crossref PubMed Scopus (2011) Google Scholar, 15Nichols B.J. Pelham H.R. Biochim. Biophys. Acta. 1998; 1404: 9-31Crossref PubMed Scopus (127) Google Scholar). NSF to SNARE complexes in the of and When is the complexes reversibly into This is thought to be for the of SNAREs fusion is SNARE complexes were in the of NSF and by the ATPase disassembly, the of SNAP-25 by the light chain of botulinum the SNAREs only in the disassembled the ternary complex is T. H. S. T. Südhof T.C. H. EMBO J. 1994; PubMed Scopus Google Scholar, H. Hanson P.I. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, H. FEBS Lett. 1994; PubMed Scopus (43) Google Scholar, H. EMBO J. 1995; PubMed Scopus (127) Google Scholar). that not only the complex the SNARE complexes are to When by NSF was SNAP-25 was in each 4, that all complexes can be disassembled by NSF and α-SNAP. In the of investigated whether and of the assembly are when synaptobrevin is by its in the synaptic complex. The cognate SNARE of are not its and its it that it with the synaptic SNAREs in that not form complexes with the and synaptobrevin were from of in syntaxin with synaptobrevin not with of was in (16Fasshauer D. Eliason W.K. Brünger A.T. Jahn R. Biochemistry. 1998; 37: 10354-10362Crossref PubMed Scopus (208) Google Scholar, 20Fasshauer D. Bruns D. Shen B. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 4582-4590Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar), used spectroscopy to changes during assembly. We that synaptobrevin is as a an α-helical assembly (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). the of was typical for proteins not Biochemistry. 8: PubMed Scopus Google Scholar). a increase in α-helical content is observed formation of the complex which is to that observed during the formation of the complex (21Fasshauer D. Otto H. Eliason W.K. Jahn R. Brünger A.T. J. Biol. Chem. 1997; 272: 28036-28041Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). These that the assembly of the complex changes similar to that of the synaptic SNARE complex. these and it be that is a preference for the formation of the complex. for formation of ternary complexes in the of equal of and The syntaxin complex was and with synaptobrevin with a of were in which only the SNARE motif of syntaxin was present in the complex with formation was by the of complexes, which were due to different in equal of each of the ternary complexes formed when synaptobrevin and were that is no preference for the cognate the non-cognate R-SNARE of whether syntaxin was In the present have that complex formation between SNARE proteins is specific than (1Rothman J.E. Nature. 1994; 372: 55-63Crossref PubMed Scopus (2011) Google Scholar, J. J.E. Bennett M.K. Scheller R.H. Neuron. 1994; Full Text PDF PubMed Scopus Google Scholar). four different and a of found that SNARE complexes can be formed in The of these complexes are similar to those of the synaptic complex with respect to assembly, disassembly, and biophysical properties, suggesting that they at least in vitro, The structure of the core domain of the synaptic SNARE complex the of layers of interacting amino acids in the core of the four helix bundle (24Sutton R.B. Fasshauer D. Jahn R. Brünger A.T. Nature. 1998; 395: 347-353Crossref PubMed Scopus (1932) Google Scholar). The the view that these are in the of SNARE showed that syntaxin can be with syntaxin major and (25Fasshauer D. Sutton R.B. Brünger A.T. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15781-15786Crossref PubMed Scopus Google Scholar), a hypothesis now by the of in complex formation between SNAREs was The between and synaptobrevin is T. G. W. Biol. Cell. 1998; 9: PubMed Scopus Google Scholar, H.R. R. Scheller R.H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), the amino acids the core layers are at least similar can be from these it is clear that the amino acids in the core are the for SNARE complex formation with the on the of the complex the of these complexes are with respect to domain conformational and These that at least the complexes investigated form supporting hypothesis that all SNARE complexes structure (25Fasshauer D. Sutton R.B. Brünger A.T. Jahn R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15781-15786Crossref PubMed Scopus Google Scholar). in these were not during are This to the that it is these that are for in with the of SNARE function in membrane fusion (3Hanson P.I. Heuser J.E. Jahn R. Curr. Opin. Neurobiol. 1997; 7: 310-315Crossref PubMed Scopus (334) Google Scholar). We conclude that no intrinsic SNAREs from complexes with each other, one of the original of the SNARE hypothesis (1Rothman J.E. Nature. 1994; 372: 55-63Crossref PubMed Scopus (2011) Google Scholar). These that one to in to the specificity in SNARE in the is that SNAREs participate in multiple in yeast M. Fischer von Mollard G. Trends Cell Biol. 1998; 8: 215-218Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 15Nichols B.J. Pelham H.R. Biochim. Biophys. Acta. 1998; 1404: 9-31Crossref PubMed Scopus (127) Google Scholar). SNAREs are specific with respect to H.R. R. Scheller R.H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J.C. J. M. Scheller R.H. J. Cell Biol. 1998; PubMed Scopus Google Scholar). is no for cognate from non-cognate SNARE complexes, of is generally as for SNAREs. We were to syntaxin together with from i.e. a in which the synaptic SNAREs and are This the view that they not with each other in to different compartments, however, such non-cognate SNAREs the during membrane to different is to non-cognate SNAREs from proteins that SNAREs with a of specificity than they each other. one of the proteins that with SNARE the protein that to the domain of as recently J. Südhof T.C. J. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google and to be a domain in the In the of SNARE complexes that is by specific proteins such as have been to with the synaptic SNARE it is not whether they would bind to of non-cognate The role of proteins to SNARE complexes to be They SNARE function at a step in the fusion in a between SNARE complexes would that by such proteins is in After of SNARE protein were by another B. L. R. M. Scheller R.H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). We for on and and for on

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