Structure of core domain of fibril-forming PHF/tau fragments

¹ Boston College
² Univ Texas at Dallas

^* To whom correspondence should be addressed. E-mail: kirschnd{at}bc.edu.

Submitted on July 7, 2005
Revised on August 12, 2005
Accepted on 14 November 2005

	Abstract

Short peptide sequences within the microtubule binding domain of the protein tau are proposed to be core nucleation sites for formation of amyloid fibrils displaying the paired helical filament (PHF) morphology characteristic of neurofibrillary tangles. To study the structure of these proposed nucleation sites, we analyzed the x-ray diffraction patterns from the assemblies formed by a variety of PHF/tau-related peptide constructs containing the motifs VQIINK ("PHF6*") in the second repeat and VQIVYK ("PHF6") in the third repeat of tau. Peptides included: tripeptide acetyl-VYK-amide (AcVYK), tetrapeptide acetyl-IVYK-amide (AcPHF4), hexapeptide acetyl-VQIVYK-amide (AcPHF6), and acetyl-GKVQIINKLDLSNVQKDNIKHGSVQIVYKPVDLSKVT-amide (AcTR4). All diffraction patterns showed reflection at spacings of 4.7 Å 3.8 Å, and ~8-10 Å, which are characteristic of an orthogonal unit cell of -sheets having dimensions a=9.4 Å, b=6.6 Å, and c=~8-10 Å (where a, b, c are the lattice constants in the H-bonding, chain, and intersheet directions). The sharp 4.7 Å reflections indicate that the crystallites are likely to be elongated along the H-bonding direction and in a cross- conformation. The assembly of the AcTR4 peptide, which contains both motifs (VQIVYK and VQIINK), consisted of twisted sheets, as indicated by a unique fanning of the diffuse equatorial scattering and meridional accentuation of the (210) reflection at 3.8 Å spacing. The diffraction data for AcVYK, AcPHF4, and AcPHF6 all indicated ~50 Å-wide tubular assemblies having double-walls, where -strands constituted the walls. In this structure the peptides are H-bonded together in the fiber direction, and the intersheet direction is radial. The positive-charged lysine residues face the aqueous medium, and tyrosine-tyrosine aromatic interactions stabilize the intersheet (double wall) layers. This particular contact, which may be involved in PHF fibril formation, is proposed here as a possible aromatic target for anti-tauopathy drugs.

Key Words: Alzheimer's disease, amyloid, fiber diffraction, paired helical filaments, protein folding, x-ray diffraction

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