Structures of Oligomeric States of Tau Protein, Amyloid-β, α-Synuclein and Prion Protein Implicated in Alzheimer's Disease, Parkinson's Disease and Prionopathies

Abstract

In this review, we focus on the biophysical and structural aspects of the oligomeric states of physiologically intrinsically disordered proteins and peptides tau, amyloid-β and α-synuclein and partly disordered prion protein and their isolations from animal models and human brains. These protein states may be the most toxic agents in the pathogenesis of Alzheimer's and Parkinson's disease. It was shown that oligomers are important players in the aggregation cascade of these proteins. The structural information about these structural states has been provided by methods such as solution and solid-state NMR, cryo-EM, crosslinking mass spectrometry, AFM, TEM, etc., as well as from hybrid structural biology approaches combining experiments with computational modelling and simulations. The reliable structural models of these protein states may provide valuable information for future drug design and therapies.

Keywords: amyloid-β; neurodegenerative diseases; oligomer; prion protein; tau protein; α-synuclein.

Figure 2

Models of Aβ oligomers. (A) Sequence of Aβ1–42. (B) The arrangement of different Aβ molecules contributing to the tetramer with β sheets 1–3 shown (top); overlay of models from PDB ID 6RHY (bottom). (C) Representative snapshots of simulations illustrating the extent of the polar defect and conformational deviation for each oligomer model. Models without layered β-sheet edges (0pe = 0 β1-strand pair edges; further numbers indicate the number of β1, β2 and β3 strands)—are shown that do not form stable pores. Bottom row: Models of β barrel pores without exposed edges, based on scaffold structures 3SGO and 2OTK/5W4J respectively [44]. (D) Model of Aβ hexameric pore and its collisional cross section (CCS) on the scale of measured values (red line) [45]. (E) X-ray crystallographic structure of macrocyclic peptide mimic of Aβ 17–36 reported by Spencer et al. [51]. From top: β-hairpin monomer; trimer, hexamer and dodecamer observed. At the scheme on the right side of the figure, the peptide is assigned as peptide 1. PDB ID 4NTR. (F) X-ray crystallographic structure of the trimer reported by Kreutzer et al. [50], formed by macrocyclic peptide mimic of Aβ 17–36. From top: (i) Triangular trimer where the three water molecules in the center hole of the trimer are shown as spheres (left) and detailed view of the intermolecular hydrogen bonds formed at the three corners of the triangular trimer (PDB ID 5HOX) (right); (ii) views of the dodecamer with octahedral and dodecameric shape; (iii) model for the hierarchical assembly of an Aβ β-hairpin into a trimer, dodecamer and annular pore based on the crystallographic assembly of this peptide mimic. At the scheme on the right side of the panel (E), the peptide is assigned as peptide 2. (G) X-ray crystallographic structure of the β-barrel-like tetramer formed by peptide mimic of Aβ12–40 (PDB ID 7RTZ): (i) side and top views of the tetramer; (ii) cartoon illustration of the parallel and antiparallel β-sheet interactions that stabilize the tetramer (left) and snapshots from REMD simulation of a tetramer of Aβ9–42 based on the β-barrel-like tetramer where residues 12–22 and 30–40 are constrained to the crystallographic coordinates (right); (iii) snapshot from the MD simulation showing 24% occupancy of water molecules within the pore over last 400 ns of the trajectory as blue mesh [48]. (H) (Top from the left) Superposition of the 10 models of Aβcc oligomers with the lowest Rosetta scores: Dimensions of the hexamer barrel with the loop and core regions indicated. (Bottom from the left) Simplified representation of the hexamer topology. Packing of C-terminal residues I41 and A42 in the hydrophobic core. Hairpin loop stabilizing D23-K28 salt bridge [54].

Figure 3

MD obtained Aβ oligomer models. (A) Trimers of C-terminal Aβ tandem repeat fragments. Left to right: Aβ(24–34), Aβ(25–35) and Aβ(26–36) GG in cylindrical conformation. Adapted from [56]. (B) Initial out-of-register antiparallel starting conformation of Aβ(25–35) and final octamer conformation after MD simulation. Adapted from [56]. (C) Top and side views of Aβ42 oligomers generated by Heligeom59 (Penta0 and Hexa0) and by MD simulations (Penta1, Penta2, Hexa1 and Hexa2). The C-terminal residues Ala42 are represented in an orange sphere. Adapted from [58]. (D) Two most populated clusters of Aβ42 tetramer. Adapted from [63]. (E) MD-refined [69] β-barrel conformation of tetrameric Aβ40 (MD starting conformation) (top); free-energy landscape of tetrameric Aβ42 with respect to the top conformation using AMBER99SB-DISP and residues 11–28 and 30–42 (bottom). Adapted from [64] with permission from ACS. (F) Representative structures of AlphaFold2 predicted structures of Aβ42 oligomers (from dimer to hexamer) showing the helical interface made by the C-terminus. Adapted from [66].

Figure 5

Oligomers of α-synuclein. (A) Sequence (3 lines correspond to 3 domains of αS, with 7 imperfect KTKEGV repeats shown bold and underlined) and schema of domain organization of αS. (B) SAXS-derived structure of the αS oligomer. Adapted from [112]. (C) 10S αS oligomer subgroup (blue) and 15S oligomer subgroup (grey). Adapted from [113]. (D) Binding of type A* and type B* oligomers with membranes, where type B* oligomers insert their rigid β-sheet rich regions into the lipid bilayers and therefor disrupt their integrity. Adapted from [114] with permission from the American Association for the Advancement of Science. (E) 3D reconstruction of αS oligomers. Adapted from [115]. (F) SAXS-based model of αS oligomers showing the compact core in blue surrounded by disordered fuzzy coat shown in green. The cryoEM density map is shown inside the oligomer core (gray). Adapted from [115]. (G) Circular (top row) and linear/helical/extended (bottom 2 rows) oligomeric structures. Adapted from [118]. (H) XL-DMD structural model of the αS dimer. Adapted from [119]. (I) MD obtained model of α-synuclein dimer, produced by docking of Monte Carlo produced monomers. Adapted from [120] with permission from Elsevier.

Figure 6

Structure of PrP and its oligomers. (A) NMR structure for wildtype human prion protein (PrP residues 91–231) PED00045, PDB 5YJ5, 20 conformers. The sequence of human PrP is shown on top of the figure with highlighted octapeptide repeats and cysteine positions. (B) Domain swapped dimer of PrP, PDB ID 1I4M. (C) Oligomer composed of PrP peptides, PDB ID 4E1H. (D) PrP^β dimer structure obtained by short-distance crosslinking constraint-guided discrete molecular dynamics; intra-protein crosslinks (magenta) and inter-protein crosslinks (green) (top). Residue deuteration values are superimposed on the representative predicted structure of the PrP^β monomer. Intra-protein crosslinks (magenta) (bottom). Adapted from [145]. (E) Representation of all intra- and inter-protein constraints obtained by crosslinking a 1:1 equimolar mixture of ¹⁴N- and ¹⁵N-PrP^β. Adapted from [145]. (F) Model of PrP trimer. (G) Model of PrP tetramer.

Figure 7

Tau protein and its oligomers. (A) Schema of 6 CNS tau isoforms grouped between 4R and 3R isoforms together with their domain organization: I1, I2 represent N-terminal inserts, P1, P2 proline rich regions, R1-R4 microtubule binding repeats (MTBR), R’ region following repeats of lower sequence homology with repeats. (B) Snapshots of four meta-stable aggregates seen in the pre-nucleation phase of the 12-chain VQIVYK run at low concentration. V309 residues are shown in green, V306, I308 and Y310 in red. Adapted from [171]. (C–E) Atomic structures of K18 and K19 octamers, averaged from the last 5-ns MD simulations. Models are divided into three groups according to the conformation of R3 to U-K18/K19 (C), L-K18/K19 (D) and SL-K18/K19 (E) octamers. (C–E) adapted from [173].

Figure 1

Oligomer formation. (A) A schematic representation of the microscopic steps and associated reaction rate constants describing oligomer dynamics during an ongoing amyloid aggregation reaction [8]. (B) Kinetics of fibril and oligomer formation. Adapted from ref [8].

Figure 4

AFM images of Aβ oligomers. (A) Ion channel pores constituted by Aβ42. Yellow arrow points to one of the pores. Adapted from [86]. (B) AFM image of Aβ1–40 tentative oligomers showing signs of pore-like structure (Z. Bednarikova).