title: Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo.
abstract: The initiation of signaling in T lymphocytes in response to the binding of the T cell receptor (TCR) to cognate ligands is a key step in the emergence of adaptive immune responses. Conventional models posit that TCR signaling is initiated by the phosphorylation of receptor-associated immune receptor activation motifs (ITAMs). The cytoplasmic tyrosine kinase Zap70 binds to phosphorylated ITAMs, is subsequently activated, and then propagates downstream signaling. While evidence for such models is provided by experiments with cell lines, in vivo, Zap70 is bound to phosphorylated ITAMs in resting T cells. However, Zap70 is activated only upon TCR binding to cognate ligand. We report the results of computational studies of a new model for the initiation of TCR signaling that incorporates these in vivo observations. Importantly, the new model is shown to allow better and faster TCR discrimination between self-ligands and foreign ligands. The new model is consistent with many past experimental observations, and experiments that could further test the model are proposed.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Thill
authors.affiliation: Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, California, USA Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California, USA aweiss@medicine.ucsf.edu arupc@mit.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA aweiss@medicine.ucsf.edu arupc@mit.edu.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase