Structural mapping techniques distinguish the surfaces of fibrillar 1N3R and 1N4R human tau

Abstract

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Disease associated mutations in tau encode for changes in aggregate structure conformation

“…However, another possibility is that some tau mutations drive isoform-specific promotion of pathogenic tau aggregate structures or ineffectively template some tau isoforms. This is plausible given that another group has already found differences in the packed core conformations between 1N3R and 1N4R heparin-induced aggregates including an additional protease protected C-terminal sequence region for 1N3R 6 . Tau aggregate structures can also be modulated by the accelerants 77 or buffer conditions 78 of the aggregation reaction.…”

“…As a readout of aggregate structure, we used protease digestion of aggregated tau to identify tau fragments buried in the tightly packed aggregate core which are more protected from protease activity. The specific pattern of protected tau fragments has been used to detect distinct aggregate species in both recombinant tau and disease patient samples 6,7,21 .…”

“…The fibrillar forms of tau aggregates are characteristically composed of a core region containing regularly tightly packed monomer sequences rich in beta-sheet structure that are surrounded by more loosely packed or disordered N and C-terminal sequences termed the "fuzzy coat" [3][4][5] . Protease digestion of tau fibrils isolated from patient samples defined the sequences protected within the tightly packed core and suggested that 1) tau can adopt multiple conformations in fibril structures and 2) specific fibril structures tracked with individual tauopathies: Alzheimer's disease (AD), Pick's disease (PD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) [6][7][8][9][10][11][12][13][14][15] .…”

Amyloid polymorphs and pathological diversities

“…Thus, the intrinsic architectures of fibrils made even from one given protein is defined by the amyloid forming folds its constituting protein populates. This in turn defines the amino acid stretches composing the solvent exposed polypeptide chains and their distribution in space at the external surfaces of the fibrils, the surfaces through which they interact with ligands ranging from small molecules to cell components (Landureau et al, 2021;Caroux et al, 2021).…”

“…This clearly shows that the surface properties of distinct amyloid proteins define their interaction with partner proteins at the surface of neuronal cells. As structurally distinct amyloid fibrils made of one given protein expose different amino acid residues and peptide chains to the solvent (Landureau et al, 2021;Caroux et al, 2021) it appears that they will interact with different ensembles of protein partners at the surface of neuronal cells. The same holds true upon post-translational modifications of amyloid protein fibrils surfaces.…”