title: Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation.
abstract: Tau, a natively unstructured protein that regulates the organization of neuronal microtubules, is also found in high concentrations in neurofibrillary tangles of Alzheimer's disease and other neurodegenerative disorders. The conformational transition between these vastly different healthy and pathological forms remains poorly understood. We have measured residual dipolar couplings (RDCs), J-couplings, and nuclear Overhauser enhancement (NOE) in construct K18 of tau, containing all four repeat domains R1-R4. NHN RDCs were compared with prediction on the basis of a statistical model describing the intrinsic conformational sampling of unfolded proteins in solution. While local variation and relative amplitude of RDCs agrees with propensity-based prediction for most of the protein, homologous sequences in each repeat domain (DLKN, DLSN, DLSK, and DKFD in repeats R1-R4) show strong disagreement characterized by inversion of the sign of the central couplings. Accelerated molecular dynamic simulations (AMD) in explicit solvent revealed strong tendencies to form turns, identified as type I beta-turns for repeats R1-R3. Incorporation of the backbone dihedral sampling resulting from AMD into the statistical coil model closely reproduces experimental RDC values. These localized sequence-dependent conformational tendencies interrupt the propensity to sample more extended conformations in adjacent strands and are remarkably resistant to local environmental factors, as demonstrated by the persistence of the RDC signature even under harsh denaturing conditions (8 M urea). The role that this specific conformational behavior may play in the transition to the pathological form is discussed.
authors: Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors: Marco D
authors: MD
authors: Mukrasch
authors: Phineus
authors: P
authors: Markwick
authors: Jacek
authors: J
authors: Biernat
authors: Martin von
authors: Mv
authors: Bergen
authors: Pau
authors: P
authors: Bernadó
authors: Christian
authors: C
authors: Griesinger
authors: Eckhard
authors: E
authors: Mandelkow
authors: Markus
authors: M
authors: Zweckstetter
authors: Martin
authors: M
authors: Blackledge
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D016875:tau Proteins