The self-assembly ability of the first microtubule-binding repeat from tau and its modulation by phosphorylation.
Aggregation of abnormally phosphorylated tau in the form of tangs of paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. It is of fundamental importance to study the mechanism of PHF formation and its modulation by phosphorylation. In this work, we have focused on the first microtubule-binding repeat of tau encompassing an abnormal phosphorylation site Ser262. The assembly propensities of this repeat and its corresponding phosphorylated form were investigated by turbidity and electron microscopy. Additionally, conformation of the two peptides is also analyzed through circular dichroism (CD) and NMR spectroscopy. Our results reveal that both of them are capable of self-assembly and phosphorylation at Ser262 could speed up the process of assembly. A possible mechanism of PHF formation is proposed and enhancing effect of phosphorylation on assembly provides an explanation to its toxicity in Alzheimer's disease.
Zhou
Lian-Xiu
LX
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
Zeng
Zhi-Yang
ZY
Du
Jin-Tang
JT
Zhao
Yu-Fen
YF
Li
Yan-Mei
YM
D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D008854:Microscopy, Electron; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000648:ultrastructure; D010748:Phosphopeptides / Q000737:chemistry; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D010446:Peptide Fragments; D010748:Phosphopeptides; D014404:Tubulin; D016875:tau Proteins