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Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation
Moore, Christopher L. Huang, Michael H. Robbennolt, Shauna A. Voss, Kellen R. Combs, Benjamin Gamblin, Truman Chris Goux, Warren J.
Moore, Christopher L.
Huang, Michael H.
Robbennolt, Shauna A.
Voss, Kellen R.
Combs, Benjamin
Gamblin, Truman Chris
Goux, Warren J.
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Abstract
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.
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2011-12-20
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ACS
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Moore_ACS_2011.pdf
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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