title: Competing interactions stabilize pro- and anti-aggregant conformations of human Tau.
abstract: Aggregation of Tau into amyloid-like fibrils is a key process in neurodegenerative diseases such as Alzheimer. To understand how natively disordered Tau stabilizes conformations that favor pathological aggregation, we applied single-molecule force spectroscopy. Intramolecular interactions that fold polypeptide stretches of ~19 and ~42 amino acids in the functionally important repeat domain of full-length human Tau (hTau40) support aggregation. In contrast, the unstructured N terminus randomly folds long polypeptide stretches >100 amino acids that prevent aggregation. The pro-aggregant mutant hTau40ΔK280 observed in frontotemporal dementia favored the folding of short polypeptide stretches and suppressed the folding of long ones. This trend was reversed in the anti-aggregant mutant hTau40ΔK280/PP. The aggregation inducer heparin introduced strong interactions in hTau40 and hTau40ΔK280 that stabilized aggregation-prone conformations. We show that the conformation and aggregation of Tau are regulated through a complex balance of different intra- and intermolecular interactions.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.forename: Jonas
authors.initials: J
authors.lastname: Schöler
authors.forename: Christian A
authors.initials: CA
authors.lastname: Bippes
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Muller
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins