Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation
Moore, Christopher L.
Huang, Michael H.
Robbennolt, Shauna A.
Voss, Kellen R.
Gamblin, Truman Chris
Goux, Warren J.
Scholarly/refereed, author accepted manuscript
Copyright © 2011 American Chemical Society
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Tau protein was scanned for highly amyloidogenic sequences in amphiphilic motifs (X)nZ, Z(X)nZ (n≥2) or (XZ)n (n≥2), where X is a hydrophobic residue and Z is a charged or polar residue. N-acetyl peptides homologous to these sequences were used to study aggregation. Transmission electron microscopy (TEM) showed 7 peptides, in addition to well known primary nucleating sequences c275VQIINK (AcPHF6*) and Ac306VQIVYK (AcPHF6), formed fibers, tubes, ribbons or rolled sheets. Of the peptides shown by TEM to form amyloid, Ac10VME, AcPHF6*, Ac375KLTFR, and Ac393VYK were found to enhance the fraction of β-structure of AcPHF6 formed at equilibrium, and Ac375KLTFR was found to inhibit AcPHF6 and AcPHF6* aggregation kinetics in a dose-dependent manner, consistent with its participation in a hybrid steric zipper model. Single site mutants were generated which transformed predicted amyloidogenic sequences in tau into non-amyloidogenic ones. A M11K mutant had fewer filaments and showed a decrease in aggregation kinetics and an increased lag time compared to wild type tau, while a F378K mutant showed significantly more filaments. Our results infer that sequences throughout tau, in addition to PHF6 and PHF6*, can seed amyloid formation or affect aggregation kinetics or thermodynamics.
Moore, C. L., Huang, M. H., Robbennolt, S. A., Voss, K. R., Combs, B., Gamblin, T. C., & Goux, W. J. (2011). Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation. Biochemistry, 50(50), 10876–10886. http://doi.org/10.1021/bi2014745
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