RESUMEN
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.
Asunto(s)
Dominios Proteicos Ricos en Prolina , Proteínas Proto-Oncogénicas c-fyn , Receptores de N-Metil-D-Aspartato , Dominios Homologos src , Proteínas tau , N-Metilaspartato/química , Péptidos/química , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-fyn/química , Proteínas Proto-Oncogénicas c-fyn/genética , Proteínas tau/química , Proteínas tau/genética , Humanos , Receptores de N-Metil-D-Aspartato/química , Estabilidad ProteicaRESUMEN
Protein Tyrosine Phosphatase (PTP) superfamily is a key enzyme involved in the regulation of growth-related cell signaling cascades, such as the RAS/MAPK pathway, that directly affect cancer cell growth and metastasis. Several studies have indicated that the drug resistance observed in several late-stage tumors might also be affected by the levels of PTP in the cell. Hence, these phosphatases have been in the limelight for the past few decades as potential drug targets and several promising drug candidates have been developed, even though none of these drugs have reached the market yet. In this review, we explore the potential of PTP as a viable anti-cancer drug target by studying PTPs, their regulation of several key cancer cell signaling pathways, and how their levels affect various types of cancer. Furthermore, we present the current scenario of PTP as a molecular target and the various challenges faced in the development of PTP-targeting anti-cancer drugs.