TY  - JOUR
AU  - Hochmair, Janine
AU  - van den Oetelaar, Maxime C M
AU  - Ravatt, Leandre
AU  - Diez, Lisa
AU  - Lemmens, Lenne J M
AU  - Ponce-Lina, Renata
AU  - Sankar, Rithika
AU  - Franck, Maximilian
AU  - Nolte, Gesa
AU  - Semenova, Ekaterina
AU  - Mohapatra, Satabdee
AU  - Ottmann, Christian
AU  - Brunsveld, Luc
AU  - Wegmann, Susanne
TI  - Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation.
JO  - Communications biology
VL  - 8
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2025-00925
SP  - 1139
PY  - 2025
AB  - 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.
KW  - 14-3-3 Proteins: metabolism
KW  - tau Proteins: metabolism
KW  - tau Proteins: chemistry
KW  - Microtubules: metabolism
KW  - Humans
KW  - Phosphorylation
KW  - Protein Binding
KW  - Protein Aggregates
KW  - Protein Aggregation, Pathological: metabolism
KW  - 14-3-3 Proteins (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40745206
C2  - pmc:PMC12313985
DO  - DOI:10.1038/s42003-025-08548-0
UR  - https://pub.dzne.de/record/280247
ER  -