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Journal Article

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

MPS-Authors
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Ukmar-Godec,  T.
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

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Fang,  P.
Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society;

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Henneberg,  F.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Godec,  A.
Research Group of Mathematical Biophysics, MPI for Biophysical Chemistry, Max Planck Society;

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Pan,  K. T.
Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society;

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Chari,  A.
Research Group of Structural Biochemistry and Mechanisms, MPI for Biophysical Chemistry, Max Planck Society;

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Urlaub,  Henning
Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society;

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Zweckstetter,  Markus
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

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Fulltext (public)

3254930.pdf
(Publisher version), 6MB

Supplementary Material (public)

3254930-Suppl.pdf
(Supplementary material), 2MB

Citation

Ukmar-Godec, T., Fang, P., Ibáñez de Opakua, A., Henneberg, F., Godec, A., Pan, K. T., et al. (2020). Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution. Science Advances, 6(30): eaba3916. doi:10.1126/sciadv.aba3916.


Cite as: http://hdl.handle.net/21.11116/0000-0007-1736-3
Abstract
Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20S proteasome. Decline in 20S activity characterizes neurodegenerative diseases. Here, we examine 20S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer’s disease. We show that cleavage of tau by the 20S 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 20S 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 20S proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.