title: Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation.
abstract: Tau protein was scanned for highly amyloidogenic sequences in amphiphilic motifs (X)(n)Z, Z(X)(n)Z (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 seven peptides, in addition to well-known primary nucleating sequences Ac(275)VQIINK (AcPHF6*) and Ac(306)VQIVYK (AcPHF6), formed fibers, tubes, ribbons, or rolled sheets. Of the peptides shown by TEM to form amyloid, Ac(10)VME, AcPHF6*, Ac(375)KLTFR, and Ac(393)VYK were found to enhance the fraction of β-structure of AcPHF6 formed at equilibrium, and Ac(375)KLTFR 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.
authors.affiliation: Department of Chemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Moore
authors.forename: Michael H
authors.initials: MH
authors.lastname: Huang
authors.forename: Shauna A
authors.initials: SA
authors.lastname: Robbennolt
authors.forename: Kellen R
authors.initials: KR
authors.lastname: Voss
authors.forename: Benjamin
authors.initials: B
authors.lastname: Combs
authors.forename: T Chris
authors.initials: TC
authors.lastname: Gamblin
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Goux
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry; D002942:Circular Dichroism; D019281:Dimerization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000648:ultrastructure; D009842:Oligopeptides / Q000737:chemistry*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D017354:Point Mutation; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure
chemical_list: D000682:Amyloid; C054369:MAPT protein, human; D050505:Mutant Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D016875:tau Proteins
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