Single posttranslational modifications in the central repeat domains of Tau4 impact its aggregation and tubulin binding

A variety of methods has been employed to study the impact of posttranslational modifications on Tau protein function. Here, we describe a semisynthesis strategy 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 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 one inhibits tubulin polymerization but exhibits aggregation behaviour very similar to unmodified Tau. In contrast, phosphorylated Tau variants exhibit similar binding to tubulin as unmodified Tau4 but show lower tendencies to aggregate.

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