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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 molecular architecture of αSβ1 peptide in the context of the helical tape that constitutes the amphiphilic bilayer nanotube wall (colored for hydrophobic, orange; hydrophilic, cyan). a) The length of the peptide determines the tape thickness. b) The tape width is stabilized by the interdigitation of side chains and intersheet Tyr interactions as highlighted in yellow. c) The tape then extends through interstrand amide hydrogen bonding (black dashes) and intersheet interactions (Lys–Ser and Lys–Thr, blue dashes; Lys–C terminus, red dashes). Graphics generated using PyMol.12
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fig3: The molecular architecture of αSβ1 peptide in the context of the helical tape that constitutes the amphiphilic bilayer nanotube wall (colored for hydrophobic, orange; hydrophilic, cyan). a) The length of the peptide determines the tape thickness. b) The tape width is stabilized by the interdigitation of side chains and intersheet Tyr interactions as highlighted in yellow. c) The tape then extends through interstrand amide hydrogen bonding (black dashes) and intersheet interactions (Lys–Ser and Lys–Thr, blue dashes; Lys–C terminus, red dashes). Graphics generated using PyMol.12

Mentions: 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). These unit cell dimensions are consistent with the typical interatomic separations observed for the packing of short amyloid‐like peptide molecules in the β‐strand conformation. 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 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 molecular architecture of αSβ1 peptide in the context of the helical tape that constitutes the amphiphilic bilayer nanotube wall (colored for hydrophobic, orange; hydrophilic, cyan). a) The length of the peptide determines the tape thickness. b) The tape width is stabilized by the interdigitation of side chains and intersheet Tyr interactions as highlighted in yellow. c) The tape then extends through interstrand amide hydrogen bonding (black dashes) and intersheet interactions (Lys–Ser and Lys–Thr, blue dashes; Lys–C terminus, red dashes). Graphics generated using PyMol.12
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4279883&req=5

fig3: The molecular architecture of αSβ1 peptide in the context of the helical tape that constitutes the amphiphilic bilayer nanotube wall (colored for hydrophobic, orange; hydrophilic, cyan). a) The length of the peptide determines the tape thickness. b) The tape width is stabilized by the interdigitation of side chains and intersheet Tyr interactions as highlighted in yellow. c) The tape then extends through interstrand amide hydrogen bonding (black dashes) and intersheet interactions (Lys–Ser and Lys–Thr, blue dashes; Lys–C terminus, red dashes). Graphics generated using PyMol.12
Mentions: 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). These unit cell dimensions are consistent with the typical interatomic separations observed for the packing of short amyloid‐like peptide molecules in the β‐strand conformation. 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.

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.

Show MeSH