Abstract
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.