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The structure of cross-β tapes and tubes formed by an octapeptide, αSβ1.

Morris KL, Zibaee S, Chen L, Goedert M, Sikorski P, Serpell LC - Angew. Chem. Int. Ed. Engl. (2013)

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK.

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A number of short peptides and larger proteins are able to self‐assemble to form cross‐β amyloid‐like fibrils. 1 These β‐sheet peptides have been increasingly explored as potentially useful bionanomaterials due to their propensity to spontaneously assemble to form large complex structures from simple monomers. 2 An eight‐residue fragment of the amyloidogenic Parkinson’s disease related peptide α‐synuclein,3 named αSβ1, assembles to form a helical nanostructure... X‐ray fiber diffraction has been extensively used to reveal that many proteins and peptides are able to assemble to form a cross‐β structure in which β‐strands run perpendicular to the fiber axis and associate to form long‐range hydrogen‐bonded β‐sheets. 1c, 4 The inherent strength of this arrangement is underlined by the similarity to the architecture of cross‐β silks. 4a, 5 The non‐covalent self‐assembly of peptide monomers also underpins the spontaneous formation of elaborate fibrillar structures. 6 α‐Synuclein (α‐syn) is a 140‐residue peptide that assembles to form amyloid‐like fibrils that are deposited in Lewy bodies in Parkinson’s disease. 3 α‐Syn fibrils assembled in vitro have been confirmed to have a β‐sheet‐rich structure consistent with the amyloid cross‐β architecture. 7 Solid‐state NMR studies on the cross‐β amyloid core of recombinant human α‐syn fibrils have indicated sets of β‐strands at discrete positions between 30–110. 8 We have explored the assembly potential and structure of a segment of α‐syn corresponding to positions 37–44 (NH2‐VLYVGSKT‐COOH) herein referred to αSβ1... The diffraction signals expected from cross‐β structures were observed at 4.7–4.8 Å and 9.8 Å but with axial alignments different to traditional cross‐β amyloids, indicating a novel arrangement within the αSβ1 assemblies... The nanotube supramolecular structure is consistent with the XRFD data and is further consistent with the amphiphilic nature of the molecule (Figure 2 d), whereby two αSβ1 peptides stack end‐on‐end within the wall to make a bilayer of a thickness of ca. 56 Å (16 residues×3.5 Å)... The reflections measured from the film‐textured XRFD pattern were found to index to an orthorhombic unit cell of the dimensions a=9.50; b=19.92; c=27.97 Å; α=β=γ=90° (Figure S6 and Table S2)... The 4.8 Å reflection is consistent with a hydrogen bonding separation of β‐strands (half of the a dimension) and the 9.8 Å arises from spacing between β‐sheets (half of the b dimension)... The determined unit cell was found to accommodate four peptide molecules corresponding to half the amphiphilic bilayer of the nanotube wall (c=27.97 Å)... The molecular architecture of the αSβ1 peptide within this cell was explored through iterative model building of both parallel and antiparallel models... Calculated X‐ray fiber diffraction patterns were compared to experimental X‐ray data until the backbone architecture best reproduced the experimental X‐ray fiber diffraction... The model structure was minimized to orient side chains and the final model constructed as shown in Figure 3... The β‐sheet arrangement was concluded to be parallel to maintain the amphiphilicity of the nanotube wall and this model was found to be consistent with diffraction data comparisons... The relative intensities of reflections will be modulated by the exact structural architecture and side chain rotamers within the unit cell and this is difficult to exactly reproduce in this model... However, it is interesting that in this structural arrangement, stabilizing side chain interactions between peptides that rationalize the formation and stabilization of the nanotubes are also found... Taken together, the match between calculated and experimental diffraction data indicates that the unit cell and model structure are representative of the tapes that constitute the αSβ1 nanotube wall... Helical tapes and nanotubes have been observed for a number of peptidic self‐assembling monomers including Aβ(16‐22),10a,b, 13 cyclo[(‐d‐Ala‐l‐Glu‐d‐Ala‐l‐Gln‐)2],6c Lanreotide,6a A6 K,10d NDI‐lysine amphiphiles,6b KLVFF‐derived peptides,9, 10c and FFFEEE‐containing peptide amphiphiles. 14 In summary, the αSβ1 peptide assembles into flat tape structures with a repetitive separation of 4.8 Å along the tape long axis.

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The proposed model of the arrangement of αSβ1 peptides that creates a nanotubular morphology. a) Helical tapes form and close into b) mature tubes. c) The peptides are arranged out‐of‐plane with respect to the tube wall creating an amphiphilic bilayer stabilized by d) the amphiphilic nature of the αSβ1 peptide. e) The orientation of the αSβ1 strands are shown in the context of the tape then leading to the nanotubes. The single peptides are represented as lines with hydrophobicity and hydrophilicity shown as orange and cyan, respectively. The hydrophobicity of the αSβ1 sequence is shown according to the White and Wimley scale.11 Graphics generated in Pymol.12
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fig2: The proposed model of the arrangement of αSβ1 peptides that creates a nanotubular morphology. a) Helical tapes form and close into b) mature tubes. c) The peptides are arranged out‐of‐plane with respect to the tube wall creating an amphiphilic bilayer stabilized by d) the amphiphilic nature of the αSβ1 peptide. e) The orientation of the αSβ1 strands are shown in the context of the tape then leading to the nanotubes. The single peptides are represented as lines with hydrophobicity and hydrophilicity shown as orange and cyan, respectively. The hydrophobicity of the αSβ1 sequence is shown according to the White and Wimley scale.11 Graphics generated in Pymol.12

Mentions: The diffraction signals expected from cross‐β structures were observed at 4.7–4.8 Å and 9.8 Å but with axial alignments different to traditional cross‐β amyloids, indicating a novel arrangement within the αSβ1 assemblies. The texture of the fibrous alignment is complex and we hypothesize that the patterns are complicated by contributions from both nanotubes and tapes, however they exhibit azimuthal reflection angles that are consistent with the helical alignment of the 4.8 and 9.8 Å periodicities (Figure S4a). The texture of the film‐textured alignment is simpler since flattened nanotubes will contribute to diffraction in the same way as flat tapes. Interestingly however, we observe azimuthal reflection angles consistent with helices (Figure S4b), similar to observations on other nanotubular assemblies.10b, 13 Inspection of the film‐textured XRFD pattern finds that the 4.8 and 9.8 Å reflections are aligned to the equator (Figure S3b) indicating their corresponding structural periodicities are both aligned parallel to the film plane. Of particular interest, a 29 Å reflection was observed to have meridional alignment indicating that the structural periodicity it arises from is aligned perpendicular to the film plane and thus perpendicular to the αSβ1 tape long axis. The observed periodicity of 29 Å correlates well with the length of the αSβ1 peptide in a β‐strand conformation of 28 Å (8 residues×3.5 Å). Therefore, we deduce that the long axis of the αSβ1 molecule is arranged perpendicular to the αSβ1 tape long axis (Figure S5). This is corroborated by the equatorial alignment of this reflection in the fiber‐textured alignment indicating the αSβ1 molecules are aligned perpendicular to the nanotube long axis. From these observations, the molecular orientation within the assemblies can be described, as shown in Figure 2, where the long axis of the αSβ1 peptide is aligned perpendicular to tape long axis and width. The nanotube supramolecular structure is consistent with the XRFD data and is further consistent with the amphiphilic nature of the molecule (Figure 2 d), whereby two αSβ1 peptides stack end‐on‐end within the wall to make a bilayer of a thickness of ca. 56 Å (16 residues×3.5 Å).


The structure of cross-β tapes and tubes formed by an octapeptide, αSβ1.

Morris KL, Zibaee S, Chen L, Goedert M, Sikorski P, Serpell LC - Angew. Chem. Int. Ed. Engl. (2013)

The proposed model of the arrangement of αSβ1 peptides that creates a nanotubular morphology. a) Helical tapes form and close into b) mature tubes. c) The peptides are arranged out‐of‐plane with respect to the tube wall creating an amphiphilic bilayer stabilized by d) the amphiphilic nature of the αSβ1 peptide. e) The orientation of the αSβ1 strands are shown in the context of the tape then leading to the nanotubes. The single peptides are represented as lines with hydrophobicity and hydrophilicity shown as orange and cyan, respectively. The hydrophobicity of the αSβ1 sequence is shown according to the White and Wimley scale.11 Graphics generated in Pymol.12
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4279883&req=5

fig2: The proposed model of the arrangement of αSβ1 peptides that creates a nanotubular morphology. a) Helical tapes form and close into b) mature tubes. c) The peptides are arranged out‐of‐plane with respect to the tube wall creating an amphiphilic bilayer stabilized by d) the amphiphilic nature of the αSβ1 peptide. e) The orientation of the αSβ1 strands are shown in the context of the tape then leading to the nanotubes. The single peptides are represented as lines with hydrophobicity and hydrophilicity shown as orange and cyan, respectively. The hydrophobicity of the αSβ1 sequence is shown according to the White and Wimley scale.11 Graphics generated in Pymol.12
Mentions: The diffraction signals expected from cross‐β structures were observed at 4.7–4.8 Å and 9.8 Å but with axial alignments different to traditional cross‐β amyloids, indicating a novel arrangement within the αSβ1 assemblies. The texture of the fibrous alignment is complex and we hypothesize that the patterns are complicated by contributions from both nanotubes and tapes, however they exhibit azimuthal reflection angles that are consistent with the helical alignment of the 4.8 and 9.8 Å periodicities (Figure S4a). The texture of the film‐textured alignment is simpler since flattened nanotubes will contribute to diffraction in the same way as flat tapes. Interestingly however, we observe azimuthal reflection angles consistent with helices (Figure S4b), similar to observations on other nanotubular assemblies.10b, 13 Inspection of the film‐textured XRFD pattern finds that the 4.8 and 9.8 Å reflections are aligned to the equator (Figure S3b) indicating their corresponding structural periodicities are both aligned parallel to the film plane. Of particular interest, a 29 Å reflection was observed to have meridional alignment indicating that the structural periodicity it arises from is aligned perpendicular to the film plane and thus perpendicular to the αSβ1 tape long axis. The observed periodicity of 29 Å correlates well with the length of the αSβ1 peptide in a β‐strand conformation of 28 Å (8 residues×3.5 Å). Therefore, we deduce that the long axis of the αSβ1 molecule is arranged perpendicular to the αSβ1 tape long axis (Figure S5). This is corroborated by the equatorial alignment of this reflection in the fiber‐textured alignment indicating the αSβ1 molecules are aligned perpendicular to the nanotube long axis. From these observations, the molecular orientation within the assemblies can be described, as shown in Figure 2, where the long axis of the αSβ1 peptide is aligned perpendicular to tape long axis and width. The nanotube supramolecular structure is consistent with the XRFD data and is further consistent with the amphiphilic nature of the molecule (Figure 2 d), whereby two αSβ1 peptides stack end‐on‐end within the wall to make a bilayer of a thickness of ca. 56 Å (16 residues×3.5 Å).

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

A number of short peptides and larger proteins are able to self‐assemble to form cross‐β amyloid‐like fibrils. 1 These β‐sheet peptides have been increasingly explored as potentially useful bionanomaterials due to their propensity to spontaneously assemble to form large complex structures from simple monomers. 2 An eight‐residue fragment of the amyloidogenic Parkinson’s disease related peptide α‐synuclein,3 named αSβ1, assembles to form a helical nanostructure... X‐ray fiber diffraction has been extensively used to reveal that many proteins and peptides are able to assemble to form a cross‐β structure in which β‐strands run perpendicular to the fiber axis and associate to form long‐range hydrogen‐bonded β‐sheets. 1c, 4 The inherent strength of this arrangement is underlined by the similarity to the architecture of cross‐β silks. 4a, 5 The non‐covalent self‐assembly of peptide monomers also underpins the spontaneous formation of elaborate fibrillar structures. 6 α‐Synuclein (α‐syn) is a 140‐residue peptide that assembles to form amyloid‐like fibrils that are deposited in Lewy bodies in Parkinson’s disease. 3 α‐Syn fibrils assembled in vitro have been confirmed to have a β‐sheet‐rich structure consistent with the amyloid cross‐β architecture. 7 Solid‐state NMR studies on the cross‐β amyloid core of recombinant human α‐syn fibrils have indicated sets of β‐strands at discrete positions between 30–110. 8 We have explored the assembly potential and structure of a segment of α‐syn corresponding to positions 37–44 (NH2‐VLYVGSKT‐COOH) herein referred to αSβ1... The diffraction signals expected from cross‐β structures were observed at 4.7–4.8 Å and 9.8 Å but with axial alignments different to traditional cross‐β amyloids, indicating a novel arrangement within the αSβ1 assemblies... The nanotube supramolecular structure is consistent with the XRFD data and is further consistent with the amphiphilic nature of the molecule (Figure 2 d), whereby two αSβ1 peptides stack end‐on‐end within the wall to make a bilayer of a thickness of ca. 56 Å (16 residues×3.5 Å)... The reflections measured from the film‐textured XRFD pattern were found to index to an orthorhombic unit cell of the dimensions a=9.50; b=19.92; c=27.97 Å; α=β=γ=90° (Figure S6 and Table S2)... The 4.8 Å reflection is consistent with a hydrogen bonding separation of β‐strands (half of the a dimension) and the 9.8 Å arises from spacing between β‐sheets (half of the b dimension)... The determined unit cell was found to accommodate four peptide molecules corresponding to half the amphiphilic bilayer of the nanotube wall (c=27.97 Å)... The molecular architecture of the αSβ1 peptide within this cell was explored through iterative model building of both parallel and antiparallel models... Calculated X‐ray fiber diffraction patterns were compared to experimental X‐ray data until the backbone architecture best reproduced the experimental X‐ray fiber diffraction... The model structure was minimized to orient side chains and the final model constructed as shown in Figure 3... The β‐sheet arrangement was concluded to be parallel to maintain the amphiphilicity of the nanotube wall and this model was found to be consistent with diffraction data comparisons... The relative intensities of reflections will be modulated by the exact structural architecture and side chain rotamers within the unit cell and this is difficult to exactly reproduce in this model... However, it is interesting that in this structural arrangement, stabilizing side chain interactions between peptides that rationalize the formation and stabilization of the nanotubes are also found... Taken together, the match between calculated and experimental diffraction data indicates that the unit cell and model structure are representative of the tapes that constitute the αSβ1 nanotube wall... Helical tapes and nanotubes have been observed for a number of peptidic self‐assembling monomers including Aβ(16‐22),10a,b, 13 cyclo[(‐d‐Ala‐l‐Glu‐d‐Ala‐l‐Gln‐)2],6c Lanreotide,6a A6 K,10d NDI‐lysine amphiphiles,6b KLVFF‐derived peptides,9, 10c and FFFEEE‐containing peptide amphiphiles. 14 In summary, the αSβ1 peptide assembles into flat tape structures with a repetitive separation of 4.8 Å along the tape long axis.

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