Secondary Nucleating Sequences Affect Kinetics and Thermodynamics of Tau Aggregation

详细信息    查看全文

• 作者：Christopher L. Moore ; Michael H. Huang ; Shauna A. Robbennolt ; Kellen R. Voss ; Benjamin Combs ; T. Chris Gamblin ; Warren J. Goux
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：December 20, 2011
• 年：2011
• 卷：50
• 期：50
• 页码：10876-10886
• 全文大小：650K
• 年卷期：v.50,no.50(December 20, 2011)
• ISSN：1520-4995

文摘

Tau protein was scanned for highly amyloidogenic sequences in amphiphilic motifs (X)_nZ, Z(X)_nZ (n 鈮?2), or (XZ)_n (n 鈮?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 Ac²⁷⁵VQIINK (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 尾-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.