Myristoylation, a Protruding Loop, and Structural Plasticity Are Essential Features of a Nonenveloped Virus Fusion Peptide Motif

Members of the fusion-associated small transmembrane (FAST) protein family are a distinct class of membrane fusion proteins encoded by nonenveloped fusogenic reoviruses. The 125-residue p14 FAST protein of reptilian reovirus has an ∼38-residue myristoylated N-terminal ectodomain containing a moderately apolar N-proximal region, termed the hydrophobic patch. Mutagenic analysis indicated sequence-specific elements in the N-proximal portion of the p14 hydrophobic patch affected cell-cell fusion activity, independent of overall effects on the relative hydrophobicity of the motif. Circular dichroism (CD) of a myristoylated peptide representing the majority of the p14 ectodomain suggested this region is mostly disordered in solution but assumes increased structure in an apolar environment. From NMR spectroscopic data and simulated annealing, the soluble nonmyristoylated p14 ectodomain peptide consists of an N-proximal extended loop flanked by two proline hinges. The remaining two-thirds of the ectodomain peptide structure is disordered, consistent with predictions based on CD spectra of the myristoylated peptide. The myristoylated p14 ectodomain peptide, but not a nonmyristoylated version of the same peptide nor a myristoylated scrambled peptide, mediated extensive lipid mixing in a liposome fusion assay. Based on the lipid mixing activity, structural plasticity, environmentally induced conformational changes, and kinked structures predicted for the p14 ectodomain and hydrophobic patch (all features associated with fusion peptides), we propose that the majority of the p14 ectodomain is composed of a fusion peptide motif, the first such motif dependent on myristoylation for membrane fusion activity. Members of the fusion-associated small transmembrane (FAST) protein family are a distinct class of membrane fusion proteins encoded by nonenveloped fusogenic reoviruses. The 125-residue p14 FAST protein of reptilian reovirus has an ∼38-residue myristoylated N-terminal ectodomain containing a moderately apolar N-proximal region, termed the hydrophobic patch. Mutagenic analysis indicated sequence-specific elements in the N-proximal portion of the p14 hydrophobic patch affected cell-cell fusion activity, independent of overall effects on the relative hydrophobicity of the motif. Circular dichroism (CD) of a myristoylated peptide representing the majority of the p14 ectodomain suggested this region is mostly disordered in solution but assumes increased structure in an apolar environment. From NMR spectroscopic data and simulated annealing, the soluble nonmyristoylated p14 ectodomain peptide consists of an N-proximal extended loop flanked by two proline hinges. The remaining two-thirds of the ectodomain peptide structure is disordered, consistent with predictions based on CD spectra of the myristoylated peptide. The myristoylated p14 ectodomain peptide, but not a nonmyristoylated version of the same peptide nor a myristoylated scrambled peptide, mediated extensive lipid mixing in a liposome fusion assay. Based on the lipid mixing activity, structural plasticity, environmentally induced conformational changes, and kinked structures predicted for the p14 ectodomain and hydrophobic patch (all features associated with fusion peptides), we propose that the majority of the p14 ectodomain is composed of a fusion peptide motif, the first such motif dependent on myristoylation for membrane fusion activity. Complex, multimeric viral fusion proteins mediate the fusion of viral envelopes to target cell membranes during virus entry into cells (1White J.M. Annu. Rev. Physiol. 1990; 52: 675-697Crossref PubMed Scopus (416) Google Scholar). Membrane destabilization during the fusion process is dependent on a fusion peptide motif contained within these enveloped virus fusion proteins (2Blumenthal R. Clague M.J. Durell S.R. Epand R.M. Chem. Rev. 2003; 103: 53-69Crossref PubMed Scopus (243) Google Scholar, 3Epand R.M. Biochim. Biophys. Acta. 2003; 1614: 116-121Crossref PubMed Scopus (234) Google Scholar, 4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). Fusion peptides are moderately hydrophobic stretches of ∼20 amino acids, frequently rich in glycine and alanine residues (3Epand R.M. Biochim. Biophys. Acta. 2003; 1614: 116-121Crossref PubMed Scopus (234) Google Scholar, 5Epand R.M. Epand R.F. Martin I. Ruysschaert J. Biochemistry. 2001; 40: 8800-8807Crossref PubMed Scopus (48) Google Scholar, 6Skehel J.J. Cross K. Steinhauer D. Wiley D.C. Biochem. Soc. Trans. 2001; 29: 623-626Crossref PubMed Scopus (61) Google Scholar). In the case of the class I fusion proteins typified by influenza hemagglutinin (HA), 1The abbreviations used are: HA, hemagglutinin; FAST, fusion-associated small transmembrane; MD, molecular dynamics; TOCSY, total correlation spectroscopy; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; E-COSY, exclusive correlated spectroscopy; HP, hydrophobic patch; RRV, reptilian reovirus; LUV, large unilamellar vesicle; DOPC, 1,2-dioleoyl-sn-glycerol-3-phosphocholine; DOPE, 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine. human immunodeficiency virus gp41, and the F proteins of paramyxoviruses, the fusion peptide motifs are located at the N terminus of the fusion polypeptide (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). Conversely, these motifs are embedded internally within the amino acid sequence of the class II fusion proteins (e.g. alphaviruses and flaviviruses) and the G protein of vesicular stomatitis virus (VSV) (7Whitt M.A. Zagouras P. Crise B. Rose J.K. J. Virol. 1990; 64: 4907-4913Crossref PubMed Google Scholar, 8Shome S.G. Kielian M. Virology. 2001; 279: 146-160Crossref PubMed Scopus (12) Google Scholar). Structural predictions for fusion peptides based on CD or infrared spectroscopy have yielded conflicting results (9Martin I. Defrise-Quertain F. Decroly E. Vandenbranden M. Brasseur R. Ruysschaert J.-M. Biochim. Biophys. Acta. 1993; 1145: 124-133Crossref PubMed Scopus (110) Google Scholar, 10Lüneberg J. Martin I. Nussler F. Ruysschaert J.-M. Herrmann A. J. Biol. Chem. 1995; 270: 27606-27614Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 11Martin I. Schaal H. Scheid A. Ruysschaert J.-M. J. Virol. 1996; 70: 298-304Crossref PubMed Google Scholar, 12Yang J. Gabrys C.M. Weliky D.P. Biochemistry. 2001; 40: 8126-8137Crossref PubMed Scopus (111) Google Scholar) and are influenced by the different methods used for preparation of the water-insoluble, flexible fusion peptide (13Han X. Tamm L.K. Proc. Natl. Acad. Sci. 2000; 97: 13097-13102Crossref PubMed Scopus (131) Google Scholar). The properties of conformational flexibility and environmentally induced structural changes may represent essential features of fusion peptides, intimately linked to their function in the fusion process (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar, 14Davies S.M. Kelly S.M. Price N.C. Bradshaw J.P. FEBS Lett. 1998; 425 (S. M. A.): 415-418Crossref PubMed Scopus (25) Google Scholar, 15Pécheur E.-I. Martin I. Bienvenüe A. Ruysschaert J.-M. Hoekstra D. J. Biol. Chem. 2000; 275: 3936-3942Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). To deal with the issues of peptide solubility and environmental effects on peptide structure, Han et al. (16Han X. Bushweller J.H. Cafiso D.S. Tamm L.K. Biol. 2001; PubMed Scopus Google Scholar) used a peptide to the influenza virus fusion peptide structural of the fusion peptide by NMR spectroscopy in the of a hydrophobic The structure is by an N-terminal and a at and the the of the fusion peptide not a structure at a at (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar, X. Bushweller J.H. Cafiso D.S. Tamm L.K. Biol. 2001; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). are and hydrophobic residues on the of the structure to a hydrophobic The of the N-terminal a of glycine residues that has to an essential of fusion (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). influenza HA, the structures of fusion peptides are the of the class II fusion in the of the ectodomain of these proteins K. J. J. PubMed Scopus Google Scholar, A. A. B. J. Kielian M. PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar). the class I fusion peptides, the class II fusion to flexible structures in the and A. A. B. J. Kielian M. PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar). The hydrophobic by the structure of the influenza fusion peptide is in the class II fusion peptides by a hydrophobic flanked by at the of the The loop structure may the same in different to the and changes in the structure of the class I fusion peptides (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar, A. A. B. J. Kielian M. PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar). The reovirus fusion-associated small transmembrane (FAST) proteins are a family of membrane fusion the fusion proteins encoded by nonenveloped M. R. J. 2000; PubMed Scopus Google Scholar, R. J. Virol. PubMed Scopus Google Scholar, R. J. Virol. PubMed Scopus Google Scholar). The FAST proteins represent a distinct class of membrane fusion proteins that are the enveloped virus class I and class II fusion proteins by their small M. R. J. 2000; PubMed Scopus Google Scholar, R. J. Virol. PubMed Scopus Google Scholar, R. J. Virol. PubMed Scopus Google Scholar). viral the FAST proteins not a in fusion but are to cell-cell fusion and their in or cells M. R. J. 2000; PubMed Scopus Google Scholar, R. J. Virol. PubMed Scopus Google Scholar). The reptilian reovirus p14 FAST protein is a protein with an ∼38-residue ectodomain that is myristoylated at N terminus R. J. Virol. PubMed Scopus Google Scholar). that the p14 ectodomain and sequence-specific lipid mixing and cell-cell fusion activity. Structural of ectodomain peptides by NMR and CD spectroscopy that the p14 ectodomain structural plasticity, and a moderately apolar region the N terminus of the p14 ectodomain an extended loop structure flanked by proline hinges. that of the small p14 ectodomain an myristoylated fusion peptide motif with a loop that is intimately in the membrane fusion and reovirus the of a I. J. Virol. PubMed Scopus Google Scholar) and of and cells in R. J. Virol. PubMed Scopus Google Scholar). The of p14 R. J. Virol. PubMed Scopus Google Scholar). The p14 hydrophobic patch peptide with a or an at the N The p14 scrambled peptide with a myristoylated N peptides by and to by and for of p14 and the of and R. J. Virol. PubMed Scopus Google Scholar). The used the to the to the by to the and cells used for with to the with and at with cell R. J. Virol. PubMed Scopus Google Scholar) and on a at a of used to of The relative of p14 to mediate by a assay. The of and in of by of cell at and with the of induced by p14 the The of p14 to with and and cells at for with of cell and and R. J. Virol. PubMed Scopus Google Scholar). and by and R. J. Virol. PubMed Scopus Google Scholar). cells on with p14 and cell with and and R. J. Virol. PubMed Scopus Google Scholar). cells and a and the Circular CD spectra an dichroism The peptide at of in contained in a cell that at in a cell containing the lipid first into a a solution of and The by and and the lipid to to small unilamellar with the for CD version Sci. PubMed Scopus Google Scholar). The CD data are the structure with the for Membrane of p14 peptides to lipid mixing the of et al. Hoekstra D. Biochemistry. PubMed Scopus Google Scholar) with large unilamellar composed of and M. Epand R.F. Epand R.M. R. J. Virol. PubMed Scopus Google Scholar). of with of and and a of to used in the assay. in an II and or a with the and at and solution of the peptide in p14 peptide in the of or to of in the containing or for and to the The to of p14 peptide lipid mixing at is in on and used NMR two by of peptide or of myristoylated p14 peptide in a solution of a and at with a NMR data M. J. PubMed Scopus Google K. J. Chem. Soc. Scopus Google and J. P. J. Chem. Scopus Google and J. at on a NMR data the of and for of the two for and The for NMR data a for NMR data on a NMR the peptide, the majority of the the or and to of and In not to the total of and with that with the of The used to the and are for and structural based on A. Biochemistry. 1996; PubMed Scopus Google Scholar, K. H. Biochemistry. PubMed Scopus Google Scholar) the M. FEBS Lett. PubMed Scopus Google Scholar, M. J. of the of NMR Scholar, J. M. J. PubMed Scopus Google Scholar) an extended structure and used to a total of embedded To the embedded structures with of to the simulated molecular peptide on Biochemistry. PubMed Scopus Google Scholar) to a for of total of with a total of used for the the of the for NOE, and their the of the the to their In the the to K. The structures with of total of structures that of or The overall of these structures with the J.M. PubMed Scopus Google Scholar, D.S. J.M. J. 1993; Google Scholar, R. J.M. J. 1996; A. PubMed Scopus Google Scholar). the of the of the in the of the of a Fusion in the of region of the p14 FAST protein that hydrophobic the transmembrane is the N-terminal residues of the ectodomain a region we termed the hydrophobic patch region a of glycine and alanine residues of of fusion peptides (1White J.M. Annu. Rev. Physiol. 1990; 52: 675-697Crossref PubMed Scopus (416) Google Scholar). In of an residues and or of with R. J. Virol. PubMed Scopus Google Scholar) this region is to and for membrane fusion activity. results to that the p14 a fusion peptide. the p14 is hydrophobic is for fusion peptides of enveloped (1White J.M. Annu. Rev. Physiol. 1990; 52: 675-697Crossref PubMed Scopus (416) Google Scholar). analysis the hydrophobicity of and Biol. 1996; PubMed Scopus Google the of a region of a peptide to into the of a lipid to the of the p14 has membrane we a structural and analysis of the p14 ectodomain to the properties and of the p14 in membrane The p14 a on Membrane is sequence in the fusion peptides of different enveloped these motifs are frequently to R.M. Epand R.F. Martin I. Ruysschaert J. Biochemistry. 2001; 40: 8800-8807Crossref PubMed Scopus (48) Google Scholar, J.J. Wiley D.C. Steinhauer J. 2001; PubMed Scopus Google Scholar). To the of the p14 in the of amino within this region in the of the p14 of the p14 to in by and with a of by that of the p14 to the membrane of for a of p14 in fusion to of the to the of in (e.g. protein or to the The of to mediate membrane fusion by the of in and the results a of p14 fusion this the fusion of not with the overall hydrophobicity of the hydrophobic patch fusion not with a hydrophobic motif or with a the and hydrophobic p14 and results suggested that the p14 ectodomain a sequence-specific in the fusion residues to residues within the N-proximal portion of the p14 to the and of fusion Conversely, the the of fusion mediated by to (e.g. fusion of the cell at not of with or acid fusion activity, the of this to p14 and to with the and p14 fusion The of in p14 fusion the target for a essential for cell-cell fusion R. J. Virol. PubMed Scopus Google Scholar). The of to p14 function is and is the of NMR structural The the of an the N terminus of the p14 R. J. Virol. PubMed Scopus Google the fusion an in the p14 ectodomain that is results that of the R. J. Virol. PubMed Scopus Google with not fusion is the of the and not the that to the of fusion activity. The for a at this by the fusion of the In to of a for the of residues the terminus of the The and the a of that to not Based on the we that the N-terminal myristoylation and residues within the N-proximal portion of the and an in the of a structure or the fusion process The analysis not based on of structures or a features that have essential to the of the fusion peptide of (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). the p14 an in the of small apolar residues or hydrophobic residues that an structure or a structure the a with of on and hydrophobic or residues on the the and and not this structure, these residues a sequence-specific effect the of the p14 The p14 of Structural structure of an extended p14 ectodomain peptide peptide the majority of the p14 ectodomain the p14 the residues to in peptide solubility and The peptide myristoylated at the N-terminal glycine is the case for CD spectra the peptide in a of at and a of structure The peptide an in with an analysis of the region by predicted that the hydrophobic patch of p14 Biochem. Sci. 2000; Full Text Full Text PDF Scopus Google Scholar). and to at peptide and this increased structure at peptide with peptide structures X. Tamm L.K. J. Biol. 2000; PubMed Scopus Google Scholar). at peptide the of lipid of or the in in and a to increased structure structural analysis suggested that the p14 ectodomain a flexible structure, of a structure membrane of dichroism spectroscopy of the p14 ectodomain peptide, at the indicated in in the of or in by structure predictions the spectra the and are in in in in in in in a NMR the p14 an NMR spectroscopy used to into residues the portion of the p14 a sequence-specific effect on p14 fusion activity, at the same CD analysis the p14 ectodomain is mostly nonmyristoylated version of the N-terminal peptide used for NMR at for NMR structural the myristoylated version of this peptide that structural their D.S. J. Biol. PubMed Scopus Google Scholar, D.S. FEBS Lett. PubMed Scopus Google Scholar, D.S. Biochemistry. PubMed Scopus Google Scholar, D.S. PubMed Scopus Google Scholar) and and in the to and residues to and these of the to the sequence-specific of the and residues is the that not portion of the peptide or CD a of residues and and and and and and that in of a structure in this In residues are two distinct features of the structure the of for residues to structures for this region that The is the of a that residues of the loop structures suggested the extended loop by the and of and and the and of and structural in with results and CD that predicted extensive flexibility in the p14 ectodomain and with the in the of the that and in p14 structure of or the NMR spectra of the or myristoylated p14 peptides are of structural and the of in the is of the of structural within the peptide on or spectra in The p14 of the p14 to amino acid the predicted of a loop structure, and that the p14 region are flexible are consistent with this region of p14 an essential in the membrane fusion To the p14 membrane destabilization activity, of fusion peptides (3Epand R.M. Biochim. Biophys. Acta. 2003; 1614: 116-121Crossref PubMed Scopus (234) Google of the peptide for their to mediate lipid mixing in an in assay. The peptide to large unilamellar and lipid mixing by a Hoekstra D. Biochemistry. PubMed Scopus Google Scholar). in and or the peptide mediated lipid mixing in a lipid mixing in the of peptide or to the myristoylated scrambled version of the peptide lipid mixing that the lipid mixing with dependent on the sequence of the ectodomain peptide and not to the hydrophobic of the The amino acid residues of the hydrophobic patch to lipid mixing on their the nonmyristoylated version of the peptide not mediate lipid mixing Based on these we propose that the p14 may function in an the fusion peptides of enveloped virus fusion the lipid for membrane the properties of an amino acid an loop structure, and the for the p14 fusion peptide of a p14 Fusion structural of enveloped virus fusion peptides have to the that membrane destabilization the for structural in the fusion peptide. flexibility may to peptide structures and lipid or hydrophobic peptide motifs (e.g. the transmembrane (3Epand R.M. Biochim. Biophys. Acta. 2003; 1614: 116-121Crossref PubMed Scopus (234) Google Scholar, 4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). properties of enveloped virus fusion peptides are to with the p14 Mutagenic indicated the p14 is an essential of the of fusion the p14 ectodomain has NMR spectroscopy indicated the of a loop and and CD and NMR spectroscopy suggested the ectodomain is flexible and propose that the N-terminal ectodomain of the p14 FAST protein an N-terminal fusion peptide motif linked a flexible or region to the transmembrane and the of the The p14 HP, features that the enveloped virus fusion peptides, an essential for myristoylation and an amino acid In to the class I and II enveloped virus fusion peptides, the p14 is moderately hydrophobic and is predicted to have a of into the lipid or the hydrophobicity of and Biol. 1996; PubMed Scopus Google Scholar). The that p14 membrane are dependent on the hydrophobic of the amino acid residues is by the of a correlation overall hydrophobicity of the p14 and cell-cell fusion by the of the nonmyristoylated of the p14 protein or ectodomain peptide to cell-cell membrane fusion R. J. Virol. PubMed Scopus Google Scholar) or lipid mixing propose that the the predicted loop may for the overall hydrophobicity of the p14 and function to membrane we are the p14 is the first of a fusion motif that is dependent on sequence-specific residues and a for membrane and of the p14 to Fusion p14 features with the class I and class II fusion peptides of enveloped to class I fusion peptides (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google the p14 is N-terminal and is to the of the protein by a flexible region that is disordered in an the fusion peptide to an independent class I fusion peptides a structure, the p14 is predicted to a fusion loop the class II fusion peptides A. A. B. J. Kielian M. PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar). The and residues the of the p14 loop may into the lipid to the in the extended of the class II fusion peptides are to an by in the of the lipid D. PubMed Scopus Google Scholar). and and or and are predicted to the p14 loop and may to these of the loop into the Structural of the p14 Fusion and CD spectroscopy predicted that of the p14 ectodomain is disordered in solution but may increased structure, dependent on environmental to the with membrane fusion peptides (13Han X. Tamm L.K. Proc. Natl. Acad. Sci. 2000; 97: 13097-13102Crossref PubMed Scopus (131) Google Scholar, 15Pécheur E.-I. Martin I. Bienvenüe A. Ruysschaert J.-M. Hoekstra D. J. Biol. Chem. 2000; 275: 3936-3942Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). The structural of fusion peptides is essential for their membrane S.M. Kelly S.M. Price N.C. Bradshaw J.P. FEBS Lett. 1998; 425 (S. M. A.): 415-418Crossref PubMed Scopus (25) Google Scholar, 15Pécheur E.-I. Martin I. Bienvenüe A. Ruysschaert J.-M. Hoekstra D. J. Biol. Chem. 2000; 275: 3936-3942Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). propose that the p14 is a structure in to a loop in to function a Structural of the p14 ectodomain or in the fusion The disordered region may a flexible conformational changes in the structure or of the p14 HP, to the of the region that the influenza fusion peptide to the of the polypeptide (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). Based on the CD is that the portion of the p14 disordered in the predicted NMR structure, assumes increased structure in an apolar environment. a for the fusion peptide, in the portion a a disordered structure to a at the (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar, X. Bushweller J.H. Cafiso D.S. Tamm L.K. Biol. 2001; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in to the fusion peptide, the NMR spectra that not a to essential conformational changes in the structure of the p14 HP, an consistent with the that cell-cell fusion and p14 ectodomain lipid mixing at are NMR spectroscopy of p14 to the disordered region of the p14 ectodomain a flexible assumes an structure in a membrane environment. and Membrane for an N-terminal on p14 to essential for cell-cell fusion R. J. Virol. PubMed Scopus Google Scholar). The of myristoylation not p14 membrane in the the acid may intimately in the fusion is by the of the nonmyristoylated p14 ectodomain peptide to lipid mixing the of in membrane fusion is the of with or membranes the to changes in p14 ectodomain structure or to membrane structure during the fusion is to to the structural of proteins M. D. J.M. F. PubMed Scopus Google Scholar, J. J.M. Sci. 1993; PubMed Scopus Google Scholar, J.M. J. 1996; PubMed Scopus Google Scholar). we of of myristoylated membrane proteins that the for structural is that the and apolar residues to the structure of the p14 Structural of myristoylated peptides or proteins that such amino are to an structure an J.M. J. 1996; PubMed Scopus Google Scholar, M. R. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, E. P. I. D. Proc. Natl. Acad. Sci. PubMed Scopus Google Scholar). the p14 ectodomain structure with the of the membrane in p14 is in a to the of N-terminal peptides with the of the to their the protein by Biol. PubMed Scopus Google Scholar, R. B. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). is not to of the and the N of the p14 ectodomain in the same mediated by the transmembrane and to of the p14 ectodomain the of acid not with membranes Biochim. Biophys. Acta. PubMed Scopus Google of the p14 ectodomain that may in membrane of the on p14 structure, the membrane that p14 at the fusion is the case with influenza R. D.P. J. Biol. 1996; PubMed Scopus Google of the of to to in lipid is by the increased membrane by myristoylated peptides and by the of to the of a peptide relative to the of the M. R. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. 2001; PubMed Scopus Google Scholar). structural analysis of soluble p14 ectodomain peptides a of the of in p14 structure of the structure of myristoylated and nonmyristoylated of the p14 are NMR analysis of p14 in on the of Membrane results that the majority of the p14 ectodomain is composed of a fusion peptide motif linked to the of the protein a flexible is in to the fusion peptides of enveloped are a of a is that the of membrane fusion is dependent on extensive conformational changes, are to essential for enveloped membrane In the case of enveloped extensive structural of large is in the of the fusion peptide and in the viral and target membrane into to membrane fusion (2Blumenthal R. Clague M.J. Durell S.R. Epand R.M. Chem. Rev. 2003; 103: 53-69Crossref PubMed Scopus (243) Google Scholar, 4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar). p14 is a viral is not in fusion but in a fusion protein to mediate cell-cell propose that conformational changes within the small p14 ectodomain are to in of and target may the of proteins in cell-cell The p14 may have to features to effect of the fusion to essential a a and a flexible or that the N-proximal loop the may mediate the of the p14 ectodomain with the of these apolar motifs for the membrane of the in the membrane of hydrophobic or residues lipid of lipid by changes in the or structure of the p14 such the of fusion in the of membrane fusion in R. Clague M.J. Durell S.R. Epand R.M. Chem. Rev. 2003; 103: 53-69Crossref PubMed Scopus (243) Google or fusion that are and in of the fusion process (4Tamm L.K. Biochim. Biophys. Acta. 2003; 1614: 14-23Crossref PubMed Scopus (77) Google Scholar, R. H. Biol. PubMed Scopus Google Scholar, R. 2003; Full Text Full Text PDF PubMed Scopus Google to for

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