The Lys 280 → Gln mutation mimicking disease-linked acetylation of Lys 280 in tau extends the structural core of fibrils and modulates their catalytic properties.
Amyloid fibrillar aggregates isolated from the brains of patients with neurodegenerative diseases invariably have post-translational modifications (PTMs). The roles that PTMs play in modulating the structures and polymorphism of amyloid aggregates, and hence their ability to catalyze the conversion of monomeric protein to their fibrillar structure is, however, poorly understood. This is particularly true in the case of tau aggregates, where specific folds of fibrillar tau have been implicated in specific tauopathies. Several PTMs, including acetylation at Lys 280, increase aggregation of tau in the brain, and increase neurodegeneration. In this study, tau-K18 K280Q, in which the Lys 280 → Gln mutation is used to mimic acetylation at Lys 280, is shown, using HX-MS measurements, to form fibrils with a structural core that is longer than that of tau-K18 fibrils. Measurements of critical concentrations show that the binding affinity of monomeric tau-K18 for its fibrillar counterpart is only marginally more than that of monomeric tau-K18 K280Q for its fibrillar counterpart. Quantitative analysis of the kinetics of seeded aggregation, using a simple Michaelis-Menten-like model, in which the monomer first binds and then undergoes conformational conversion to β-strand, shows that the fibrils of tau-K18 K280Q convert monomeric protein more slowly than do fibrils of tau-K18. In contrast, monomeric tau-K18 K280Q is converted faster to fibrils than is monomeric tau-K18. Thus, the effect of Lys 280 acetylation on tau aggregate propagation in brain cells is expected to depend on the amount of acetylated tau present, and on whether the propagating seed is acetylated at Lys 280 or not.
['Kumar|Harish|H|', 'Udgaonkar|Jayant B|JB|0000-0002-7005-224X']
D000107:Acetylation D019943:Amino Acid Substitution D006801:Humans D020125:Mutation, Missense D019636:Neurodegenerative Diseases D066329:Protein Aggregates D020836:Protein Structure, Quaternary D016875:tau Proteins
neurodegenerative disease kinetics seeding hydrogen-deuterium exchange mass spectrometry tau fibrils