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Initiation of T cell signaling by CD45 segregation at 'close contacts'

Chang, Veronica T; Fernandes, Ricardo A; Ganzinger, Kristina A; Lee, Steven F; Siebold, Christian; McColl, James; Jönsson, Peter LU ; Palayret, Matthieu; Harlos, Karl and Coles, Charlotte H, et al. (2016) In Nature Immunology 17(5). p.574-582
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... (More)

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.

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@article{e1c39640-c7b1-4103-8c6c-e2f7029c67aa,
  abstract     = {<p>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.</p>},
  author       = {Chang, Veronica T and Fernandes, Ricardo A and Ganzinger, Kristina A and Lee, Steven F and Siebold, Christian and McColl, James and Jönsson, Peter and Palayret, Matthieu and Harlos, Karl and Coles, Charlotte H and Jones, E Yvonne and Lui, Yuan and Huang, Elizabeth and Gilbert, Robert J C and Klenerman, David and Aricescu, A Radu and Davis, Simon J},
  issn         = {1529-2908},
  keyword      = {Crystallography, X-Ray,HEK293 Cells,Humans,Jurkat Cells,Leukocyte Common Antigens,Lymphocyte Specific Protein Tyrosine Kinase p56(lck),Microscopy, Electron,Microscopy, Fluorescence,Models, Molecular,Protein Structure, Tertiary,Receptors, Antigen, T-Cell,Signal Transduction,T-Lymphocytes,Time Factors,ZAP-70 Protein-Tyrosine Kinase,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {5},
  pages        = {574--582},
  publisher    = {Nature Publishing Group},
  series       = {Nature Immunology},
  title        = {Initiation of T cell signaling by CD45 segregation at 'close contacts'},
  url          = {http://dx.doi.org/10.1038/ni.3392},
  volume       = {17},
  year         = {2016},
}