OutlineControl of src kinase activity by Csk, CD45.pptVIP

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2017-03-25 发布于江苏
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OutlineControl of src kinase activity by Csk, CD45.ppt

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OutlineControl of src kinase activity by Csk, CD45

Outline Control of src kinase activity by Csk, CD45 Control of CD45 activity by dimerization Evidence for TCR/CD3 conformational change zeta, CD3 epsilon; TCR a/b? Partial activation and antagonism Lipid rafts and T cell activation Immune synapse or SMAC Proximal TCR signaling The yin and yang of src kinase regulation CD45 isoforms and phosphatase activity CD45 is a transmembrane phosphatase Dimerization appears to inhibit activity There are different size isoforms, created by alternative splicing of exons in the ecto domain These isoforms have different quantities of glycosylation, which may affect the degree of homo-dimerization Issue of potential ligand(s) is controversial CD45 isoform expression on B and T cells Summary: CD45 isoforms and control of lymphocyte activation Initiation of TCR Signaling:Clustering or Conformation? Models of TCR/CD3 Stoichiometry - Resting State TCR/CD3 Pre-clustering increases sensitivity to natural peptide/MHC ligands 2 - Indirect evidence for conformational change in CD3?, leading to recruitment of adaptor protein Nck Inducible binding of Nck to CD3 e Expt. setup: GST fusion with Nck SH3 domain Pull-downs from lysates of T cells (unstim. or stimulated w/different ab’s - APA 1/1 or APA 1/2) Blot for CD3 e Crosslinking the TCR With a Modified ? Chain But…full T cell activation requires both the conformational change and clustering New model: conformation and clustering Altered peptide ligands (APL) analogs of antigenic peptides usually single amino acid change (TCR contact residue) antagonists: can inhibit antigenic peptide when mixed partial agonists: stimulate subset of T cell responses e.g. cytokine release but not proliferation what properties determine differences? Lipid rafts Lipid modifications of proteins (acylation) Lipid rafts and TCR signaling Isolation of lipid rafts Work of Seed and colleagues linking lipid rafts to T cell activation: distribution +/- activation LAT palmitylation is required for TCR signaling Immune