Open access
14-3-3/Tau molecular glues modulate in vitro tau condensation
Maxime C. M. van den Oetelaar
Leandre M. Ravatt
Francisco Maqueda Zelaya
Ansgar Oberheide
Tom R. van de Wijngaart
Floor M. A. van Boxtel
Marloes A. M. Pennings
Carlo J. A. Verhoef
Thijs W. van Veldhuisen
P. Cossar
C. Ottmann
Susanne Wegmann
Luc Brunsveld
Medicine
Abstract
The intrinsically disordered protein Tau is highly phosphorylated under pathological conditions, which, among others, results in Tau liquid–liquid phase separation (LLPS), followed by aggregation. The hub protein 14-3-3 regulates Tau protein solubility and prevents LLPS by binding with phosphorylated Tau residues pS214 and pS324. Here, we report the stabilization of this Tau/14-3-3 protein–protein interaction (PPI) using reversible-covalent small-molecule molecular glues. By strengthening the 14-3-3/Tau interaction the molecular glues enhance the effect of 14-3-3 on Tau solubility in LLPS. This demonstrates the potential of modulating the 14-3-3/Tau PPI for novel drug discovery efforts in neurodegenerative diseases.