Residual structure in the repeat domain of tau: echoes of microtubule binding and paired helical filament formation.
The microtubule-associated protein tau is found aggregated into paired helical filaments in the intraneuronal neurofibrillary tangle deposits of victims of Alzheimer's disease (AD) and other related dementias. Tau contains a repeat domain consisting of three or four 31-32-residue imperfect repeats that forms the core of tau filaments and is capable of self-assembling into filaments in vitro. We have used high-resolution NMR spectroscopy to characterize the structural properties of the three-repeat domain of tau at the level of individual residues. We find that three distinct regions of the polypeptide corresponding to previously mapped microtubule interaction sites exhibit a preference for helical conformations, suggesting that these sites adopt a helical structure when bound to microtubules. In addition, we directly observe a marked preference for extended or beta-strand-like conformations in a stretch of residues between two of the helical regions, which corresponds closely to a region previously implicated as an early site of beta-strand structure formation and intermolecular interactions leading to paired helical filament (PHF) formation. This observation supports the idea that this region of the protein plays a crucial role in the formation of tau aggregates. We further show that disulfide-bond-mediated dimer formation does not affect and is not responsible for the observed structural preferences of the protein. Our results provide the first high-resolution view of the structural properties of the protein tau, are consistent with an important role for beta structure in PHF formation, and may also help explain recent reports that tau filaments contain helical structure.
Eliezer
David
D
Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. dae2005@ med.cornell.edu
Barré
Patrick
P
Kobaslija
Muris
M
Chan
Dylan
D
Li
Xiaohua
X
Heend
Lauren
L
D000595:Amino Acid Sequence; D004591:Electrophoresis, Polyacrylamide Gel; D007700:Kinetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure
D011994:Recombinant Proteins; D016875:tau Proteins