Filamentous Aggregates of Tau Proteins Fulfil Standard Amyloid Criteria Provided by the Fuzzy Oil Drop (FOD) Model

Abstract

Abnormal filamentous aggregates that are formed by tangled tau protein turn out to be classic amyloid fibrils, meeting all the criteria defined under the fuzzy oil drop model in the context of amyloid characterization. The model recognizes amyloids as linear structures where local hydrophobicity minima and maxima propagate in an alternating manner along the fibril's long axis. This distribution of hydrophobicity differs greatly from the classic monocentric hydrophobic core observed in globular proteins. Rather than becoming a globule, the amyloid instead forms a ribbonlike (or cylindrical) structure.

Keywords: Alzheimer’s disease; tau amyloid; tauopathy.

Figure 1

Theoretical (T—blue) and observed (O—red) distributions of hydrophobicity in: (A) the phf-tauO superfibril; (B,C) chains E and F as components of the phf-tauO superfibril. Orange highlighting marks residues which comprise the inter-fibril interface area (331–338).

Figure 2

Theoretical (T—blue) and observed (O—red) distributions: (A) as calculated for the proto-fibril (chains A, C, E, G and I) listed under phf-tauO; (B) for the E chain treated as a component of the proto-fibril. Orange highlighting marks residues which comprise the inter-fibril interface (331–338).

Figure 3

Theoretical (T—blue) and observed (O—red) distributions for phf-tauO: (A) chain E treated as a distinct structural unit; and (B) chain F treated as a distinct structural unit. Orange highlighting marks residues which comprise the inter-fibril interface (331–338).

Figure 4

Theoretical (T—blue) and observed (O—red) distribution for the chain E from phf-tauO (the distribution is similar in all structural units). Fragments where O significantly deviates from T are highlighted by different colors (see Table 4) that match the colors of three-dimensional (3D) presentations on Figure 5.

Figure 5

3D presentation of structures obtained using I-Tasser upper row (B–F), Robetta central row (G–K) and the fuzzy oil drop (FOD) model bottom row (L–P). The top structure (A) is the structure phf-tauO as appears in PDB database. The colors used correspond to highlights on Figure 4. Models whose status is consistent with FOD predictions (RD < 0.5) have been additionally underlined in blue (D,M,N).

Figure 6

Distribution of hydrophobicity in chain A in the Tpp in complex (T—blue, O—red, H—green): (A) when treated as a distinct structural unit; (B) when treated as a component of the complex. Good alignment between O, T, and H can be observed in the latter case.

Figure 7

T (blue) and O (red) hydrophobicity distributions in Tau (267–312) (2MZ7), revealing overall strong discordance.

Figure 8

H (green), T (blue) and O (red) distributions for selected peptides: (A) Tau (305–311), (B) Tau (306–311B); (C) for (A) and (D) for (B)—pseudo-3D view, presenting the observed hydrophobicity of a theorized structure of fibrillary tangles formed by linear propagation of the corresponding peptides. Dashed lines on (A) represent deleted residue number 11 Tau (305–311) according to data available in PDB.

Figure 9

T (blue) and O (red) profiles for the F chain from F-actin (PDB ID 3J8I), divided into two parts for visibility: 1–200 (A) and 201–375 (B). Highlighted positions mark residues that cause discordance between those distributions (on the basis of visual inspection). The remainder of the chain is regarded as accordant with the theoretical distribution. It likely contributes to the protein’s structural stability—under the assumption that a well-ordered hydrophobic core and the presence of disulfide bonds both play a role in stabilizing tertiary conformations.

Figure 10

3D presentation of F chain from F-actin (PDB ID 3J8I). Beta sheets are displayed in different shades of yellow. Red fragments distinguish residues that cause discordance between T and O distributions. These fragments correspond to highlighted parts of hydrophobicity profiles presented in Figure 9.

Figure 11

3D presentation of F chain (blue) and H chain (red) from F-actin (PDB ID 3J8I). Beta sheets are displayed in different shades of yellow (same three shades in each chain). “Stop” fragments are shown in green.