Psychedelics promote plasticity by directly binding to BDNF receptor TrkB
10 paginas, 15 fguras
Structure of SNX9 SH3 in complex with a viral ligand reveals the molecular basis of its unique specificity for alanine-containing class I SH3 motifs
Class I SH3 domain-binding motifs generally comply with the consensus sequence [R/K]x0PxxP, the hydrophobic residue 0 being proline or leucine. We have studied the unusual 0 = Ala-specificity of SNX9 SH3 by determining its complex structure with a peptide present in eastern equine encephalitis virus (EEEV) nsP3. The structure revealed the length and composition of the n-Src loop as important factors determining specificity. We also compared the affinities of EEEV nsP3 peptide, its mutants, and cellular ligands to SNX9 SH3. These data suggest that nsP3 has evolved to minimize reduction of conformational entropy upon binding, hence acquiring stronger affinity, enabling takeover of SNX9. The R…
Phosphorylated immunoreceptor tyrosine-based activation motifs and integrin cytoplasmic domains activate spleen tyrosine kinase via distinct mechanisms
Spleen tyrosine kinase (Syk) is involved in cellular adhesion and also in the activation and development of hematopoietic cells. Syk activation induced by genomic rearrangement has been linked to certain T-cell lymphomas, and Syk inhibitors have been shown to prolong survival of patients with B-cell lineage malignancies. Syk is activated either by its interaction with a double-phosphorylated immunoreceptor tyrosine-based activation motif (pITAM), which induces rearrangements in the Syk structure, or by the phosphorylation of specific tyrosine residues. In addition to its immunoreceptor function, Syk is activated downstream of integrin pathways, and integrins bind to the same region in Syk a…
Integrin cytoplasmic domain and pITAM compete for spleen tyrosine kinase binding
ABSTRACTIn hematopoietic tissues cell-cell communication involves immunoreceptors and specialized cell adhesion receptors that both mediate intracellular signals. Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in the downstream signaling of both immunoreceptors tyrosine activation motif (ITAM) receptors and integrin family cell adhesion receptors. Both phosphorylated ITAM (pITAM) and integrins bind to the regulatory domain of Syk composed of two Src homology 2 (SH2) domains. The interaction with pITAM is mediated by binding of a specific phosphotyrosine to each of the SH2 domains, leading to conformational changes and Syk kinase activation. Integrins bind to the int…
Biochemical and structural comparison of spleen tyrosine kinase interaction with integrin and the immunoreceptor tyrosine-based activation motif
Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in many different signalling pathways activated by immunoreceptors and integrins. The Syk activation mediated by phosphorylated Immunoreceptor Tyrosine-based Activation Motif (pITAM) receptors involves Src homology 2 (SH2) regulatory domains leading to Syk structural rearrangements. Differently, integrin cytoplasmic domains bind to the regulatory domain of Syk and the interaction does not require the phosphorylation, but the molecular mechanism is still unknown. This work focussed on describing the mechanism of integrin-Syk interaction and on how integrins activate Syk. First, using a fluorescent-based kinetic assay we …