title: Identification of an aggregation-prone structure of tau.
abstract: The aggregation and deposition of normally soluble proteins is the hallmark of several devastating neurodegenerative disorders. For proteins such as tau in Alzheimer's disease and α-synuclein in Parkinson's disease, aggregation involves a transition from an intrinsically disordered monomer to a highly structured fiber. While understanding the role of these proteins in neurodegeneration requires elucidation of the structural basis of self-association, the conformational heterogeneity of disordered proteins makes their structural characterization inherently challenging. Here we use single molecule Förster resonance energy transfer to measure the conformational ensemble of tau in the absence and presence of heparin to identify critical conformational changes relevant to the initiation of aggregation. We find that different domains of tau display distinct conformational properties that are strongly correlated with their degree of disorder and that may relate to their roles in aggregation. Moreover, we observe that heparin binding induces a distinct two-state structural transition in tau characterized by a loss of long-range contacts and a concomitant compaction of the microtubule binding domain. Our results describe a conformational intermediate of tau that precedes the formation of aggregates and could serve as a target for tau-focused therapeutics.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520-8114, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Elbaum-Garfinkle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000925:Anticoagulants / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects*; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D016875:tau Proteins; D006493:Heparin