title: Initiation of assembly of tau(273-284) and its ΔK280 mutant: an experimental and computational study.
abstract: The microtubule associated protein tau is essential for the development and maintenance of the nervous system. Tau dysfunction is associated with a class of diseases called tauopathies, in which tau is found in an aggregated form. This paper focuses on a small aggregating fragment of tau, (273)GKVQIINKKLDL(284), encompassing the (PHF6*) region that plays a central role in tau aggregation. Using a combination of simulations and experiments, we probe the self-assembly of this peptide, with an emphasis on characterizing the early steps of aggregation. Ion-mobility mass spectrometry experiments provide a size distribution of early oligomers, TEM studies provide a time course of aggregation, and enhanced sampling molecular dynamics simulations provide atomistically detailed structural information about this intrinsically disordered peptide. Our studies indicate that a point mutation, as well the addition of heparin, lead to a shift in the conformations populated by the earliest oligomers, affecting the kinetics of subsequent fibril formation as well as the morphology of the resulting aggregates. In particular, a mutant associated with a K280 deletion (a mutation that causes a heritable form of neurodegeneration/dementia in the context of full length tau) is seen to aggregate more readily than its wild-type counterpart. Simulations and experiment reveal that the ΔK280 mutant peptide adopts extended conformations to a greater extent than the wild-type peptide, facilitating aggregation through the pre-structuring of the peptide into a fibril-competent structure.
authors.affiliation: Department of Physics, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Larini
authors.forename: Megan Murray
authors.initials: MM
authors.lastname: Gessel
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
mesh_terms: D000595:Amino Acid Sequence; D006493:Heparin / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D017384:Sequence Deletion; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016875:tau Proteins; D006493:Heparin