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000173317 0247_ $$2doi$$a10.1074/jbc.M114.560920
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000173317 037__ $$aFZJ-2014-06727
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000173317 1001_ $$0P:(DE-HGF)0$$aGruning, C. S. R.$$b0
000173317 245__ $$aAlternative Conformations of the Tau Repeat Domain in Complex with an Engineered Binding Protein
000173317 260__ $$aBethesda, Md.$$bSoc.$$c2014
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000173317 520__ $$aThe aggregation of tau into paired helical filaments is involved in the pathogenesis of several neurodegenerative diseases including Alzheimer disease. The aggregation reaction is characterized by conformational conversion of the repeat domain, which partially adopts a cross-β structure in the resulting amyloid-like fibrils. Here we report the selection and characterization of an engineered binding protein, β-wrapin TP4, targeting the tau repeat domain. TP4 was obtained by phage display using the four-repeat tau construct K18ΔK280 as a target. TP4 binds K18ΔK280 as well as the longest isoform of human tau, htau40, with nanomolar affinity. NMR spectroscopy identified two alternative TP4-binding sites in the four-repeat domain, each including two hexapeptide motifs with high β-sheet propensity. Both binding sites contain the aggregation-determining PHF6 hexapeptide within repeat 3. In addition, one binding site includes the PHF6* hexapeptide within repeat 2, whereas the other includes the corresponding hexapeptide tau(337-342) within repeat 4, denoted PHF6**. Comparison of TP4-binding with tau aggregation reveals that the same regions of tau are involved in both processes. TP4 inhibits tau aggregation at substoichiometric concentration, demonstrating that it interferes with aggregation nucleation. This study provides residue-level insight into the interaction of tau with an aggregation inhibitor and highlights the structural flexibility of tau.
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000173317 7001_ $$0P:(DE-HGF)0$$aMirecka, E. A.$$b1
000173317 7001_ $$0P:(DE-Juel1)145785$$aKlein, A. N.$$b2
000173317 7001_ $$0P:(DE-HGF)0$$aMandelkow, E.$$b3
000173317 7001_ $$0P:(DE-Juel1)132029$$aWillbold, D.$$b4
000173317 7001_ $$0P:(DE-HGF)0$$aMarino, S. F.$$b5
000173317 7001_ $$0P:(DE-Juel1)132023$$aStoldt, M.$$b6
000173317 7001_ $$0P:(DE-HGF)0$$aHoyer, W.$$b7$$eCorresponding Author
000173317 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.M114.560920$$gVol. 289, no. 33, p. 23209 - 23218$$n33$$p23209 - 23218$$tThe @journal of biological chemistry$$v289$$x1083-351X$$y2014
000173317 8564_ $$uhttp://www.jbc.org/content/early/2014/06/25/jbc.M114.560920
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