Journal Article

DZNE-2025-00925

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation.

Hochmair, J. (First author)DZNE* ; van den Oetelaar, M. C. M. ; Ravatt, L.DZNE* ; Diez, L.DZNE* ; Lemmens, L. J. M. ; Ponce-Lina, R. ; Sankar, R.DZNE* ; Franck, M.DZNE* ; Nolte, G.DZNE* ; Semenova, E.DZNE* ; Mohapatra, S.DZNE* ; Ottmann, C. ; Brunsveld, L. ; Wegmann, S. (Last author)DZNE*

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s42003-025-08548-0

Abstract: The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3ζ enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3ζ activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3ζ concentrations, or in the presence of other 14-3-3ζ binding partners, multivalent electrostatic interactions promote Tau:14-3-3ζ co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3ζ interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.

Keyword(s): 14-3-3 Proteins: metabolism (MeSH) ; tau Proteins: metabolism (MeSH) ; tau Proteins: chemistry (MeSH) ; Microtubules: metabolism (MeSH) ; Humans (MeSH) ; Phosphorylation (MeSH) ; Protein Binding (MeSH) ; Protein Aggregates (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; 14-3-3 Proteins ; tau Proteins ; Protein Aggregates ; MAPT protein, human

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Contributing Institute(s):

1. Protein Actions in Neurodegeneration (AG Wegmann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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