Journal Article

DZNE-2020-01280

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution

Ukmar-Godec, T. (First author)DZNE* ; Fang, P. ; Ibanez de Opakua, A.DZNE* ; Henneberg, F. ; Godec, A. ; Pan, K.-T. ; Cima Omori, M. S.DZNE* ; Chari, A. ; Mandelkow, E.DZNE* ; Urlaub, H. ; Zweckstetter, M. (Last author)DZNE*

2020
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.aba3916

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.

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Contributing Institute(s):

1. Göttingen common (Göttingen common)
2. Translational Structural Biology (AG Zweckstetter)
3. Structural Principles of Neurodegeneration (AG Mandelkow 1)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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