8KDX

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

Summary for 8KDX

• Entry DOI: 10.2210/pdb8kdx/pdb
• Descriptor: Tyrosine-protein kinase Fyn, Microtubule-associated protein tau (3 entities in total)
• Functional Keywords: alzheimer's disease, fyn kinase, sh3 domain, tau protein and pxxp motif., peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 8497.20

Authors

Padavattan, S.,Jos, S. (deposition date: 2023-08-10, release date: 2024-02-28)

Primary citation

Jos, S.,Poulose, R.,Kambaru, A.,Gogoi, H.,Dalavaikodihalli Nanjaiah, N.,Padmanabhan, B.,Mehta, B.,Padavattan, S.
Tau-S214 Phosphorylation Inhibits Fyn Kinase Interaction and Increases the Decay Time of NMDAR-mediated Current.
J.Mol.Biol., 436:168445-168445, 2024

PubMed Abstract: 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.

PubMed: 38218365
DOI: 10.1016/j.jmb.2024.168445

Experimental method

X-RAY DIFFRACTION (1.01 Å)