Initiation of assembly of tau(273-284) and its ΔK280 mutant: an experimental and computational study

• Published in: Physical chemistry chemical physics : PCCP 2013-06, Vol.15 (23), p.8916-8928
• Main Authors: Larini, Luca, Gessel, Megan Murray, LaPointe, Nichole E, Do, Thanh D, Bowers, Michael T, Feinstein, Stuart C, Shea, Joan-Emma
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Heparin - metabolism; Humans; Molecular Dynamics Simulation; Point Mutation; Protein Conformation; Protein Multimerization; Sequence Deletion; tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; tau Proteins - ultrastructure; Tauopathies - genetics; Tauopathies - metabolism
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c3cp00063j

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.