Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution.

Abstract

Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20<i>S</i> proteasome. Decline in 20<i>S</i> activity characterizes neurodegenerative diseases. Here, we examine 20<i>S</i> degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer's disease. We show that cleavage of tau by the 20<i>S</i> proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline-directed Ca²⁺/calmodulin-dependent protein kinase II inhibits degradation by the 20<i>S</i> proteasome. Phosphorylation of tau by GSK3β, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20<i>S</i> proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.