Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

Ackmann, JanaBruege, AlinaGotina, LizavetaLim, SungsuJahreis, KathrinVollbrecht, Anna-LenaKim, Yun KyungPae, Ae NimLabus, JosephinePonimaskin, Evgeni
Issue Date
BioMed Central
Cell Communication and Signaling, v.22, no.1
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 Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex.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 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.
CYCLIN-DEPENDENT KINASE-5; G-PROTEIN; PHOSPHORYLATED TAU; DYSFUNCTION; MUTATIONS; ALGORITHM; ISOFORMS; MOTIFS; LIGAND; CHARMM; Protein-protein complex; Interaction interface; Serotonin receptor 7 (5-HT7R); Cyclin-dependent kinase 5 (CDK5); Tau protein (Tau) and tauopathy; Site-directed mutagenesis; Computational modeling
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