Microtubule-associated protein tau (MAPT) PHF6 motif (PHF6)

The PHF6 motif is a hexapeptide sequence (VQIVYK) located within the third microtubule-binding repeat (R3) of the microtubule-associated protein tau (MAPT). It is recognized as a primary driver of tau protein aggregation into paired helical filaments (PHFs) and neurofibrillary tangles, which are pathological hallmarks of Alzheimer's disease and other tauopathies (von Bergen et al., 2000, PNAS). Under pathological conditions, this motif transitions from a disordered state to a beta-sheet conformation, facilitating the nucleation and elongation of tau fibrils (Seidler et al., 2018, Nat Comm). Because of its central role in the initiation of tau pathology, the PHF6 motif is a major therapeutic target for small molecules and peptide-based inhibitors designed to prevent or reverse tau aggregation. Drugs targeting this motif, such as hydromethylthionine, aim to stabilize the monomeric form of tau or sterically hinder the interaction between tau molecules. Successful modulation of this motif could potentially slow the progression of neurodegeneration by reducing the proteotoxic burden of tau aggregates in the brain (Wischik et al., 2015, J Alzheimers Dis).

Other names

VQIVYKTau hexapeptide motifPHF6 hexapeptideTau R3 hexapeptide

Inhibition of tau protein aggregation by binding to the PHF6 motif to prevent the formation of cross-beta sheet structures and paired helical filaments.