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Single Posttranslational Modifications in the Central Repeat Domains of Tau4 Impact its Aggregation and Tubulin Binding
Author(s) -
Ellmer Doris,
Brehs Manuel,
HajYahya Mahmood,
Lashuel Hilal A.,
Becker Christian F. W.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201805238
Subject(s) - semisynthesis , chemistry , phosphoserine , tubulin , posttranslational modification , phosphorylation , biochemistry , tau protein , biophysics , microtubule , stereochemistry , enzyme , microbiology and biotechnology , biology , serine , medicine , disease , pathology , alzheimer's disease
A variety of methods have been employed to study the impact of posttranslational modifications on Tau protein function. Here, a semisynthesis strategy is described that enables selective modification within the central repeat domain of Tau4 (residues 291‐321), comprising a major interaction motive with tubulin as well as one of the key hexapeptides involved in Tau aggregation. This strategy has led to the preparation of four semisynthetic Tau variants with phosphoserine residues in different positions and one with a so far largely ignored carboxymethyllysine modification that results from a non‐enzymatic posttranslational modification (nPTM). The latter modification inhibits tubulin polymerization but exhibits an aggregation behavior very similar to unmodified Tau. In contrast, phosphorylated Tau variants exhibit similar binding to tubulin as unmodified Tau4 but show lower tendencies to aggregate.