Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure.
We have searched for a minimal interaction motif in tau protein that supports the aggregation into Alzheimer-like paired helical filaments. Digestion of the repeat domain with different proteases yields a GluC-induced fragment comprising 43 residues (termed PHF43), which represents the third repeat of tau plus some flanking residues. This fragment self assembles readily into thin filaments without a paired helical appearance, but these filaments are highly competent to nucleate bona fide PHFs from full-length tau. Probing the interactions of PHF43 with overlapping peptides derived from the full tau sequence yields a minimal hexapeptide interaction motif of (306)VQIVYK(311) at the beginning of the third internal repeat. This motif coincides with the highest predicted beta-structure potential in tau. CD and Fourier transform infrared spectroscopy shows that PHF43 acquires pronounced beta structure in conditions of self assembly. Point mutations in the hexapeptide region by proline-scanning mutagenesis prevent the aggregation. The data indicate that PHF assembly is initiated by a short fragment containing the minimal interaction motif forming a local beta structure embedded in a largely random-coil protein.
von Bergen
M
M
Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany.
Friedhoff
P
P
Biernat
J
J
Heberle
J
J
Mandelkow
E M
EM
Mandelkow
E
E
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry; D017354:Point Mutation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016875:tau Proteins