Journal Article

DZNE-2025-00158

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation.

Chakraborty, P.Extern* ; Zweckstetter, M. (Last author)DZNE*

2025
Springer Nature [London]

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41467-025-56028-0

Abstract: 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.

Keyword(s): tau Proteins: metabolism (MeSH) ; tau Proteins: chemistry (MeSH) ; tau Proteins: genetics (MeSH) ; Tacrolimus Binding Proteins: metabolism (MeSH) ; Tacrolimus Binding Proteins: genetics (MeSH) ; Humans (MeSH) ; Molecular Chaperones: metabolism (MeSH) ; HSP90 Heat-Shock Proteins: metabolism (MeSH) ; HSP90 Heat-Shock Proteins: genetics (MeSH) ; Prostaglandin-E Synthases: metabolism (MeSH) ; Prostaglandin-E Synthases: genetics (MeSH) ; Protein Binding (MeSH) ; Molecular Docking Simulation (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Protein Aggregates (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Scattering, Small Angle (MeSH) ; HSP40 Heat-Shock Proteins (MeSH) ; tau Proteins ; Tacrolimus Binding Proteins ; tacrolimus binding protein 5 ; Molecular Chaperones ; HSP90 Heat-Shock Proteins ; Prostaglandin-E Synthases ; MAPT protein, human ; DNAJA1 protein, human ; Protein Aggregates ; HSP40 Heat-Shock Proteins

---

Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

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

Appears in the scientific report 2025

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---