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Title (Primary) Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation
Author Mukrasch, M.D.; Markwick, P.; von Bergen, M.; Bernado, P.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M.; Blackledge, M.;
Journal Journal of the American Chemical Society
Year 2007
Department PROTEOM;
Volume 129
Issue 16
Language englisch;
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 -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.
ID 2090
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=2090
Mukrasch, M.D., Markwick, P., von Bergen, M., Bernado, P., Griesinger, C., Mandelkow, E., Zweckstetter, M., Blackledge, M. (2007):
Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation
J. Am. Chem. Soc. 129 (16), 5235 - 5243