Jump to main content
Jump to site search

Issue 23, 2013
Previous Article Next Article

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

Author affiliations

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, 273GKVQIINKKLDL284, 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.

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

Back to tab navigation

Supplementary files

Publication details

The article was received on 07 Jan 2013, accepted on 07 Mar 2013 and first published on 08 Mar 2013


Article type: Paper
DOI: 10.1039/C3CP00063J
Citation: Phys. Chem. Chem. Phys., 2013,15, 8916-8928
  •   Request permissions

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

    L. Larini, M. M. Gessel, N. E. LaPointe, T. D. Do, M. T. Bowers, S. C. Feinstein and J. Shea, Phys. Chem. Chem. Phys., 2013, 15, 8916
    DOI: 10.1039/C3CP00063J

Search articles by author

Spotlight

Advertisements