8QDV

Structure of 14-3-3 zeta delta C with the bivalent tau-pS214-pS324 peptide

Summary for 8QDV

• Entry DOI: 10.2210/pdb8qdv/pdb
• Descriptor: 14-3-3 protein zeta/delta, Microtubule-associated protein tau (3 entities in total)
• Functional Keywords: 14-3-3 zeta, tau, protein-protein interaction, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 112776.83

Authors

van den Oetelaar, M.C.M.,Brunsveld, L.,Ottmann, C. (deposition date: 2023-08-30, release date: 2024-09-11, Last modification date: 2025-09-24)

Primary citation

Hochmair, J.,van den Oetelaar, M.C.M.,Ravatt, L.,Diez, L.,Lemmens, L.J.M.,Ponce-Lina, R.,Sankar, R.,Franck, M.,Nolte, G.,Semenova, E.,Mohapatra, S.,Ottmann, C.,Brunsveld, L.,Wegmann, S.
Stoichiometric 14-3-3 zeta binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation.
Commun Biol, 8:1139-1139, 2025

PubMed 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.

PubMed: 40745206
DOI: 10.1038/s42003-025-08548-0

Experimental method

X-RAY DIFFRACTION (2.5 Å)