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@ARTICLE{Gruning:173317,
      author       = {Gruning, C. S. R. and Mirecka, E. A. and Klein, A. N. and
                      Mandelkow, E. and Willbold, D. and Marino, S. F. and Stoldt,
                      M. and Hoyer, W.},
      title        = {{A}lternative {C}onformations of the {T}au {R}epeat
                      {D}omain in {C}omplex with an {E}ngineered {B}inding
                      {P}rotein},
      journal      = {The journal of biological chemistry},
      volume       = {289},
      number       = {33},
      issn         = {1083-351X},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2014-06727},
      pages        = {23209 - 23218},
      year         = {2014},
      abstract     = {The aggregation of tau into paired helical filaments is
                      involved in the pathogenesis of several neurodegenerative
                      diseases including Alzheimer disease. The aggregation
                      reaction is characterized by conformational conversion of
                      the repeat domain, which partially adopts a cross-β
                      structure in the resulting amyloid-like fibrils. Here we
                      report the selection and characterization of an engineered
                      binding protein, β-wrapin TP4, targeting the tau repeat
                      domain. TP4 was obtained by phage display using the
                      four-repeat tau construct K18ΔK280 as a target. TP4 binds
                      K18ΔK280 as well as the longest isoform of human tau,
                      htau40, with nanomolar affinity. NMR spectroscopy identified
                      two alternative TP4-binding sites in the four-repeat domain,
                      each including two hexapeptide motifs with high β-sheet
                      propensity. Both binding sites contain the
                      aggregation-determining PHF6 hexapeptide within repeat 3. In
                      addition, one binding site includes the PHF6* hexapeptide
                      within repeat 2, whereas the other includes the
                      corresponding hexapeptide tau(337-342) within repeat 4,
                      denoted PHF6**. Comparison of TP4-binding with tau
                      aggregation reveals that the same regions of tau are
                      involved in both processes. TP4 inhibits tau aggregation at
                      substoichiometric concentration, demonstrating that it
                      interferes with aggregation nucleation. This study provides
                      residue-level insight into the interaction of tau with an
                      aggregation inhibitor and highlights the structural
                      flexibility of tau.},
      cin          = {ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {452 - Structural Biology (POF2-452)},
      pid          = {G:(DE-HGF)POF2-452},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000341017200057},
      doi          = {10.1074/jbc.M114.560920},
      url          = {https://juser.fz-juelich.de/record/173317},
}