Abstract
Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer's and Pick's diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar 'kinked hairpin' folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer's or Pick's disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.
Highlights
The ordered assembly of tau protein into amyloid filaments defines a number of neurodegenerative diseases, known as tauopathies; they are the most common proteinopathies of the human nervous system (Goedert et al, 2017)
Six tau isoforms ranging from 352 to 441 amino acids are expressed in adult human brain from a single MAPT gene (Goedert et al, 1989)
Our results show that heparin-induced 2N4R filaments consist of a mixture of at least four different conformations, whereas heparin-induced 2N3R filaments mainly adopt a single conformation
Summary
The ordered assembly of tau protein into amyloid filaments defines a number of neurodegenerative diseases, known as tauopathies; they are the most common proteinopathies of the human nervous system (Goedert et al, 2017). Six tau isoforms ranging from 352 to 441 amino acids are expressed in adult human brain from a single MAPT gene (Goedert et al, 1989) They differ by the presence or absence of inserts of 29 or 58 amino acids (encoded by exons 2 and 3, with exon three being only transcribed in conjunction with exon 2) in the N-terminal half, and the inclusion, or not, of the second 31 amino acid microtubule-binding repeat (R2), encoded by exon 10, in the C-terminal half. The core is made of amino acids 273/304–380, comprising the carboxyl-terminal parts of R1 and R2, all of R3 and R4, as well as part of the C-terminal domain This is consistent with the presence of all six tau isoforms in AD filaments (Goedert et al, 1992). These findings indicate that tau filament structures are even more versatile than previously thought, and illustrate how EM can be used to compare the structures of tau filaments from model systems with those formed in disease
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