TY  - JOUR
AU  - Chakraborty, Pijush
AU  - Zweckstetter, Markus
TI  - Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00158
SP  - 669
PY  - 2025
AB  - The pathological deposition of tau and amyloid-beta into insoluble amyloid fibrils are pathological hallmarks of Alzheimer's disease. Molecular chaperones are important cellular factors contributing to the regulation of tau misfolding and aggregation. Here we reveal an Hsp90-independent mechanism by which the co-chaperone p23 as well as a molecular complex formed by two co-chaperones, p23 and FKBP51, modulates tau aggregation. Integrating NMR spectroscopy, SAXS, molecular docking, and site-directed mutagenesis we reveal the structural basis of the p23-FKBP51 complex. We show that p23 specifically recognizes the TPR domain of FKBP51 and interacts with tau through its C-terminal disordered tail. We further show that the p23-FKBP51 complex binds tau to form a dynamic p23-FKBP51-tau trimeric complex that delays tau aggregation and thus may counteract Hsp90-FKBP51 mediated toxicity. Taken together, our findings reveal a co-chaperone mediated Hsp90-independent chaperoning of tau protein.
KW  - tau Proteins: metabolism
KW  - tau Proteins: chemistry
KW  - tau Proteins: genetics
KW  - Tacrolimus Binding Proteins: metabolism
KW  - Tacrolimus Binding Proteins: genetics
KW  - Humans
KW  - Molecular Chaperones: metabolism
KW  - HSP90 Heat-Shock Proteins: metabolism
KW  - HSP90 Heat-Shock Proteins: genetics
KW  - Prostaglandin-E Synthases: metabolism
KW  - Prostaglandin-E Synthases: genetics
KW  - Protein Binding
KW  - Molecular Docking Simulation
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Protein Aggregates
KW  - Protein Aggregation, Pathological: metabolism
KW  - Scattering, Small Angle
KW  - HSP40 Heat-Shock Proteins
KW  - tau Proteins (NLM Chemicals)
KW  - Tacrolimus Binding Proteins (NLM Chemicals)
KW  - tacrolimus binding protein 5 (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - Prostaglandin-E Synthases (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - DNAJA1 protein, human (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - HSP40 Heat-Shock Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39809798
C2  - pmc:PMC11733250
DO  - DOI:10.1038/s41467-025-56028-0
UR  - https://pub.dzne.de/record/275936
ER  -