Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R.
Computational modeling
Cyclin‐dependent kinase 5 (CDK5)
Interaction interface
Protein–protein complex
Serotonin receptor 7 (5-HT7R)
Site-directed mutagenesis
Tau protein (Tau) and tauopathy
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
19 Apr 2024
19 Apr 2024
Historique:
received:
07
12
2023
accepted:
11
04
2024
medline:
20
4
2024
pubmed:
20
4
2024
entrez:
19
4
2024
Statut:
epublish
Résumé
Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.
Sections du résumé
BACKGROUND
BACKGROUND
Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology.
METHODS
METHODS
Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex.
RESULTS
RESULTS
We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model.
CONCLUSIONS
CONCLUSIONS
Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.
Identifiants
pubmed: 38641599
doi: 10.1186/s12964-024-01612-y
pii: 10.1186/s12964-024-01612-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
233Subventions
Organisme : Hannover Biomedical Research School - Graduate School of Excellence
ID : StrucMed-Scholarship
Organisme : Hannover Biomedical Research School - Graduate School of Excellence
ID : StrucMed-Scholarship
Organisme : Hannover Biomedical Research School - Graduate School of Excellence
ID : StrucMed-Scholarship
Organisme : Korea Institute of Science and Technology Information (KISTI-HPC)
ID : KSC-2022-CRE-0435
Organisme : Korea Institute of Science and Technology Information (KISTI-HPC)
ID : KSC-2022-CRE-0435
Organisme : Korea Institute Science and Technology (KIST) institutional Program
ID : 2E32161
Organisme : Korea Institute Science and Technology (KIST) institutional Program
ID : 2E32161
Organisme : Deutsche Forschungsgemeinschaft
ID : LA4465
Organisme : Deutsche Forschungsgemeinschaft
ID : PO732
Informations de copyright
© 2024. The Author(s).
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