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Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding
Author(s) -
HajYahya Mahmood,
Gopinath Pushparathinam,
Rajasekhar Kolla,
Mirbaha Hilda,
Diamond Marc I.,
Lashuel Hilal A.
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201913001
Subject(s) - hyperphosphorylation , microtubule , phosphorylation , tau protein , microtubule polymerization , binding site , biophysics , microbiology and biotechnology , chemistry , binding domain , biology , biochemistry , tubulin , alzheimer's disease , disease , medicine
The consistent observation of phosphorylated tau in the pathology of Alzheimer's disease has contributed to the emergence of a model where hyperphosphorylation triggers both tau disassociation from microtubules and its subsequent aggregation. Herein, we applied a total chemical synthetic approach to site‐specifically phosphorylate the microtubule binding repeat domain of tau (K18) at single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues. We show that hyperphosphorylation of K18 inhibits 1) its aggregation in vitro, 2) its seeding activity in cells, 3) its binding to microtubules, and 4) its ability to promote microtubule polymerization. The inhibition increased with increasing the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. Our results argue against the hyperphosphorylation hypothesis and underscore the importance of revisiting the role of site‐specific hyperphosphorylation in regulating tau functions in health and disease.