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. 2014 Sep 10;136(36):12682-90.
doi: 10.1021/ja505713y. Epub 2014 Aug 26.

A fibril-like assembly of oligomers of a peptide derived from β-amyloid

Johnny D Pham  1 , Ryan K Spencer, Kevin H Chen, James S Nowick
Affiliations

A fibril-like assembly of oligomers of a peptide derived from β-amyloid

Johnny D Pham et al. J Am Chem Soc. .

Abstract

A macrocyclic β-sheet peptide containing two nonapeptide segments based on Aβ(15-23) (QKLVFFAED) forms fibril-like assemblies of oligomers in the solid state. The X-ray crystallographic structure of macrocyclic β-sheet peptide 3 was determined at 1.75 Å resolution. The macrocycle forms hydrogen-bonded dimers, which further assemble along the fibril axis in a fashion resembling a herringbone pattern. The extended β-sheet comprising the dimers is laminated against a second layer of dimers through hydrophobic interactions to form a fibril-like assembly that runs the length of the crystal lattice. The second layer is offset by one monomer subunit, so that the fibril-like assembly is composed of partially overlapping dimers, rather than discrete tetramers. In aqueous solution, macrocyclic β-sheet 3 and homologues 4 and 5 form discrete tetramers, rather than extended fibril-like assemblies. The fibril-like assemblies of oligomers formed in the solid state by macrocyclic β-sheet 3 represent a new mode of supramolecular assembly not previously observed for the amyloidogenic central region of Aβ. The structures observed at atomic resolution for this peptide model system may offer insights into the structures of oligomers and oligomer assemblies formed by full-length Aβ and may provide a window into the propagation and replication of amyloid oligomers.

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Figures

Figure 1
Figure 1
X-ray crystallographic structure of macrocyclic β-sheet peptide 3. Two conformers (A and B) make up the asymmetric unit.
Figure 2
Figure 2
X-ray crystallographic structure of the hydrogen-bonded dimer of macrocyclic β-sheet peptide 3. (A) Cartoon illustration of the hydrogen-bonded dimer. (B) The LFA face of the hydrogen-bonded dimer, bearing the side chains of residues Q15, L17, F19, A21, and D23 of the Aβ15–23 peptide strands and Q15′, L17′, and D23′ of the Aβ15–23 hybrid strands. (C) The VF face of the hydrogen-bonded dimer, bearing the side chains of residues K16, V18, FI20, and E22 of the Aβ15–23 peptide strands and K16′, V18′, and E22′ of the Aβ15–23 hybrid strands.
Figure 3
Figure 3
Assembly of hydrogen-bonded dimers in the X-ray crystallographic structure of macrocyclic β-sheet peptide 3. (A) Extended β-sheet that runs the length of the crystal lattice. (B) Packing of the extended β-sheets to form a two-layered structure.
Figure 4
Figure 4
(A) Interaction between the Hao amino acids at the interface between dimers in the X-ray crystallographic structure of macrocyclic β-sheet peptide 3. (B) Hydrophobic core formed by the side chains of the V18, FI20, and V18′ residues, between the layers of the extended β-sheets in the X-ray crystallographic structure of macrocyclic β-sheet 3.
Figure 5
Figure 5
Hydrogen-bonded dimers formed by macrocyclic β-sheet peptides 3–5 in aqueous solution. Key NOEs associated with dimerization and folding are shown with red and blue arrows. (3: X18 = V, X20 = FI; 4: X18 = V, X20 = F; 5: X18 = T, X20 = Y).
Figure 6
Figure 6
Illustration of the tetramer formed by macrocyclic β-sheet peptides 3–5 in aqueous solution. The tetramer forms as a sandwich-like assembly of two hydrogen-bonded dimers, sandwiched through the LFA faces (3: X18 = V, X20 = FI; 4: X18 = V, X20 = F; 5: X18 = T, X20 = Y).
Figure 7
Figure 7
Cartoon representations of fibrils formed by Aβ. (A) Parallel β-sheet fibril composed of U-shaped turns in a staggered arrangement, observed for Aβ1–40. (B) Antiparallel β-sheet fibril composed of U-shaped turns, observed for the Iowa mutant Aβ1–40. (C) Fibril-like assembly of oligomers composed of β-hairpins, that we propose from the X-ray crystallographic structure of macrocyclic β-sheet peptide 3. The green and pink colors represent the central and C-terminal regions of Aβ.
Figure 8
Figure 8
Cartoon representations of U-shaped turns (A) and β-hairpins (B) composed of Aβ. In the U-shaped turns, the faces of the β-strands pack together., In the proposed β-hairpins, the edges of the β-strands hydrogen bond together. The green and pink colors represent the central and C-terminal regions of Aβ.
Figure 9
Figure 9
Interfaces between Aβ15–23 observed in the solid state and in solution. (A) Interface between monomer subunits within the dimer of macrocyclic β-sheet peptide 3 in the solid state. (B) Interface between monomer subunits within the dimer of macrocyclic β-sheet 3 in aqueous solution. (C) Interface between the dimers of macrocyclic β-sheet 3 in the solid state. In (A) and (B) the interface occurs between the Aβ15–23 peptide strands; in (C) the interface occurs between the Aβ15–23 hybrid strands.
Figure 10
Figure 10
Supramolecular assemblies of macrocyclic β-sheet peptides derived from Aβ15–23. (A) Tetramer of 1a observed in the solid state (PDB: 4IVH). (B) Tetramer of 1b (and 1a) observed in aqueous solution. (C) Fibril-like assembly of dimers of 3 observed in the solid state.
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