title: A functional role for intrinsic disorder in the tau-tubulin complex.
abstract: Tau is an intrinsically disordered protein with an important role in maintaining the dynamic instability of neuronal microtubules. Despite intensive study, a detailed understanding of the functional mechanism of tau is lacking. Here, we address this deficiency by using intramolecular single-molecule Förster Resonance Energy Transfer (smFRET) to characterize the conformational ensemble of tau bound to soluble tubulin heterodimers. Tau adopts an open conformation on binding tubulin, in which the long-range contacts between both termini and the microtubule binding region that characterize its compact solution structure are diminished. Moreover, the individual repeats within the microtubule binding region that directly interface with tubulin expand to accommodate tubulin binding, despite a lack of extension in the overall dimensions of this region. These results suggest that the disordered nature of tau provides the significant flexibility required to allow for local changes in conformation while preserving global features. The tubulin-associated conformational ensemble is distinct from its aggregation-prone one, highlighting differences between functional and dysfunctional states of tau. Using constraints derived from our measurements, we construct a model of tubulin-bound tau, which draws attention to the importance of the role of tau's conformational plasticity in function.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.|Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Melo
authors.affiliation: Department of Physics, Yale University, New Haven, CT 06520.
authors.forename: Juliana
authors.initials: J
authors.lastname: Coraor
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.
authors.forename: Garrett
authors.initials: G
authors.lastname: Alpha-Cobb
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.
authors.forename: Shana
authors.initials: S
authors.lastname: Elbaum-Garfinkle
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nath
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; elizabeth.rhoades@sas.upenn.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
mesh_terms: D000818:Animals; D001665:Binding Sites; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D064267:Intrinsically Disordered Proteins; D046912:Multiprotein Complexes; D014404:Tubulin; D016875:tau Proteins
keywords: Alzheimer’s disease; intrinsically disordered proteins; microtubule-associated protein; single-molecule FRET; tauopathies