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          Institute: Max-Planck-Arbeitsgruppen für strukturelle Molekularbiologie     Collection: Arbeitsgruppe Zytoskelett     Display Documents



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ID: 333628.0, Max-Planck-Arbeitsgruppen für strukturelle Molekularbiologie / Arbeitsgruppe Zytoskelett
Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation
Authors:Mukrasch, M. D.; Markwick, P.; Biernat, J.; von Bergen, M.; Bernado, P.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M.; Blackledge, M.
Language:English
Date of Publication (YYYY-MM-DD):2007-04-25
Title of Journal:Journal of the American Chemical Society
Journal Abbrev.:J Am Chem Soc
Volume:129
Issue / Number:16
Start Page:5235
End Page:5243
Review Status:not specified
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Alzheimer Disease/etiology/metabolism; Amino Acid Sequence; Humans; Molecular Sequence Data; Protein Folding; Protein Structure, Secondary; tau Proteins/*chemistry/genetics
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:Max-Planck-Arbeitsgruppen für strukturelle Molekularbiologie/Zytoskelett
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