1. Initiation of T cell signaling by CD45 segregation at ‘close contacts’
- Author
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Davis, SJ, Chang, VT, Fernandes, RA, Ganzinger, KA, Lee, SF, Siebold, C, McColl, M, Jonsson, P, Palayret, M, Harlos, K, Coles, CH, Jones, EY, Lui, Y, Huang, E, Gilbert, RJC, Klenerman, D, Aricescu, AR, Lee, Steven [0000-0003-4492-5139], Klenerman, David [0000-0001-7116-6954], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Models, Molecular ,Time Factors ,T cell ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Protein tyrosine phosphatase ,Biology ,Crystallography, X-Ray ,Jurkat cells ,Article ,03 medical and health sciences ,Jurkat Cells ,Journal Article ,medicine ,Immunology and Allergy ,Humans ,Receptor ,ZAP-70 Protein-Tyrosine Kinase ,Kinase ,Research Support, Non-U.S. Gov't ,HEK 293 cells ,T-cell receptor ,Cell biology ,Protein Structure, Tertiary ,Microscopy, Electron ,030104 developmental biology ,medicine.anatomical_structure ,HEK293 Cells ,Microscopy, Fluorescence ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Leukocyte Common Antigens ,Signal transduction ,Signal Transduction - Abstract
It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.
- Published
- 2016