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Principal Investigator: Charles Scott Craik
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $568,644
Funding agency: National Institute on Aging
Abstract. A devastating class of untreatable, neurodegenerative disorders, which includes progressive
supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease (AD), are associated with
accumulation of neurofibrillary tangles (NFTs) in the brain. These aggregates are primarily composed of
microtubule-associated protein tau (MAPT/tau), which is heavily modified by post-translational modifications
(PTMs). If we understood how neurons normally regulate tau’s PTMs, we might be able to find ways of restoring
its delicate balance. The objective of this project is to understand how the molecular chaperones, heat shock
protein 70 (Hsp70) and heat shock protein 90 (Hsp90), direct modifications on tau. Hsp70 and Hsp90 are known
to bind key, aggregation-prone locations in tau. While these interactions improve the solubility of tau, they also
recruit a number of critical PTM enzymes including: (i) the E3 ubiquitin ligase CHIP, (ii) the cis-trans prolyl
isomerase FKBP51 and (iii) the protein phosphatase PP5. Specifically, each of these enzymes contains a
tetratricopeptide repeat (TPR) domain, which has affinity for the conserved EEVD-CO2H motif at the C-termini
of Hsp70 and Hsp90. Thus, we hypothesize that complexes between chaperones and TPR domains ultimately
determines tau’s conformation and whether it is ubiquitinated or de-phosphorylated. Thanks to innovations in
cryo-EM and recent breakthroughs in large-scale peptide libraries and antibody design, we are poised to use
structural and chemical approaches to understand how chaperones coordinate with TPR proteins to modify tau.
In preliminary studies, we have measured binding of the chaperone’s EEVD motifs to a panel of TPR domains,
revealing unexpected selectivity of Hsp70 for PP5 and Hsp90 for FKBP51, as well as a key role for
phosphorylation in tuning these affinities. We have also created a library of ~640,000 peptide sequences and
used it to identify a potent (<10 nM) inhibitor of CHIP’s TPR domain that does not bind closely related TPRs.
Finally, we have validated a structural approach to studying the Hsp70-CHIP-tau ternary complex, a project
which has already uncovered a surprising, essential role for ADP. Guided by these exciting findings and fueled
by a team-based approach, we propose to study how tau interacts with: (SA1) Hsp70/Hsp90-CHIP, (SA2)
Hsp90-FKBP51 and (SA3) Hsp70-PP5. Through this effort, we aim to determine how molecular switches at the
key protein interfaces tune the structure and modifications on tau. We anticipate that these studies could also
revealing new drug targets for treating tauopathies.
Terms: <70-kD Heat-Shock Protein><AD dementia><Affinity><Agonist><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Animals><Architecture><Attention><Binding><Binding Sites><Biochemical><Brain><Brain Nervous System><C-terminal><Cell Body><Cells><Chaperone><Chemicals><Client><Collaborations><Combining Site><Complex><Corticodentatonigral degeneration with neuronal achromasia><Cryo-electron Microscopy><Cryoelectron Microscopy><Crystallographies><Crystallography><Degenerative Neurologic Disorders><Dephosphorylation><Development><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Electron Cryomicroscopy><Encephalon><Engineering><Engineering / Architecture><Ensure><Enzyme Gene><Enzymes><Equilibrium><FK506 binding protein 5><FKBP51><FKBP54><Genetic><Goals><HSP 70><HSP-90><HSP70><HSP90><Heat-Shock Proteins 70><Heat-Shock Proteins 90><Individual><Kinases><Laboratories><Learning><Libraries><Location><MAPT gene><MAPT protein><MSPI protein><MT-bound tau><MTBT1><Maps><Measures><Modeling><Modification><Molecular><Molecular Chaperones><Molecular Interaction><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurofibrillary Tangles><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><PP5><PP5 phosphatase><PP5 protein-serine-threonine phosphatase><PPIase><Pathologic><Peptide Domain><Peptide Library><Peptide antibodies><Peptidyl-Prolyl cis-trans-Isomerase><Peptidylproline cis-trans-isomerase><Peptidylprolyl Isomerase><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphoric Monoester Hydrolases><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Senile Degenerative Dementia><Process><Progressive Supranuclear Ophthalmoplegia><Progressive Supranuclear Palsy><Proline Isomerase><Proline Rotamase><Proline-Rich Domain><Proline-Rich Region><Prolyl Isomerase><Protein Dephosphorylation><Protein Domains><Protein Modification><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphorylation><Protein phosphatase><Proteins><Proteomics><Quality Control><Reactive Site><Role><Scanning><Solubility><Steele-Richardson-Olszewski Disease><Steele-Richardson-Olszewski Syndrome><Structure><TFPI-2><Tauopathies><Tertiary Protein Structure><Transphosphorylases><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Work><abnormally aggregated tau protein><balance><balance function><combinatorial><cortical basal degeneration><cortico-basal degeneration><corticobasal degeneration><cryo-EM><cryoEM><cryogenic electron microscopy><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><filamentous tau inclusion><hsp70 Family><hsp90 Family><hyper-phosphorylated tau><hyperphosphorylated tau><improved><inhibitor><innovate><innovation><innovative><matrix-associated serine protease inhibitor><microtubule associated protein tau><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-associated protein tau><microtubule-bound tau><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurological degeneration><neuronal><neuronal degeneration><neuropathologic tau><neuropathological tau><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><p-tau><p-τ><paired helical filament of tau><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><peptide aminoacid sequence><peptide sequence><phospho-tau><phospho-τ><phosphorylated tau><placenta-specific protein 5><placental protein 5><post-translational modification of tau><posttranslational modification of tau><primary degenerative dementia><protein aminoacid sequence><protein homeostasis><protein phosphatase 5><protein protein interaction><proteostasis><recruit><self-aggregate tau><senile dementia of the Alzheimer type><social role><tacrolimus binding protein 5><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau conformation><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau interaction><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><tissue factory pathway inhibitor-2><tissue-factor-pathway inhibitor 2><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><τ Proteins><τ aggregation><τ conformation><τ interaction><τ phosphorylation>