Tau-S214 Phosphorylation Inhibits Fyn Kinase Interaction and Increases the Decay Time of NMDAR-mediated Current.

Autor: Jos S; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Poulose R; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Kambaru A; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Gogoi H; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Dalavaikodihalli Nanjaiah N; Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Padmanabhan B; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India., Mehta B; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India. Electronic address: bhupeshmehta@nimhans.ac.in., Padavattan S; Department of Biophysics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India. Electronic address: s.padavattan@gmail.com.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2024 Feb 15; Vol. 436 (4), pp. 168445. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1016/j.jmb.2024.168445
Abstrakt: Fyn kinase SH3 domain interaction with PXXP motif in the Tau protein is implicated in AD pathology and is central to NMDAR function. Among seven PXXP motifs localized in proline-rich domain of Tau protein, tandem 5th and 6th PXXP motifs are critical to Fyn-SH3 domain interaction. Here, we report the crystal structure of Fyn-SH3 -Tau (207-221) peptide consisting of 5th and 6th PXXP motif complex to 1.01 Å resolution. Among five AD-specific phosphorylation sites encompassing the 5th and 6th PXXP motifs, only S214 residue showed interaction with SH3 domain. Biophysical studies showed that Tau (207-221) with S214-phosphorylation (pS214) inhibits its interaction with Fyn-SH3 domain. The individual administration of Tau (207-221) with/without pS214 peptides to a single neuron increased the decay time of evoked NMDA current response. Recordings of spontaneous NMDA EPSCs at +40 mV indicate an increase in frequency and amplitude of events for the Tau (207-221) peptide. Conversely, the Tau (207-221) with pS214 peptide exhibited a noteworthy amplitude increase alongside a prolonged decay time. These outcomes underscore the distinctive modalities of action associated with each peptide in the study. Overall, this study provides insights into how Tau (207-221) with/without pS214 affects the molecular framework of NMDAR signaling, indicating its involvement in Tau-related pathogenesis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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