Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress

Author:

Jiang Lulu1ORCID,Chakraborty Pijush2ORCID,Zhang Lushuang1ORCID,Wong Melissa1ORCID,Hill Shannon E.3ORCID,Webber Chelsea Joy1,Libera Jenna1ORCID,Blair Laura J.3ORCID,Wolozin Benjamin145ORCID,Zweckstetter Markus26ORCID

Affiliation:

1. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.

2. German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany.

3. Department of Molecular Medicine, College of Medicine, Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33612, USA.

4. Center for Neurophotonics, Boston University, Boston, MA 02215, USA.

5. Center for Systems Neuroscience, Boston University, Boston, MA 02215, USA.

6. Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Am Faßberg 11, 37077 Göttingen, Germany.

Abstract

Alzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance–based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network–based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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1. Regulation of tau by peptidyl-prolyl isomerases;Current Opinion in Structural Biology;2024-02

2. ALPHAFOLD: REVOLUTIONIZING PROTEIN FOLDING THROUGH DEEP LEARNING AND NEURAL NETWORKS;İstanbul Ticaret Üniversitesi Fen Bilimleri Dergisi;2023-12-31

3. p23-FKBP51 chaperone complex regulates tau aggregation;2023-12-27

4. DnaJs are enriched in tau regulators;International Journal of Biological Macromolecules;2023-12

5. Engineering vascularized organotypic tissues via module assembly;International Journal of Extreme Manufacturing;2023-10-11

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