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

DOI: 10.1038/ni.3392

Authors: Veronica T Chang (Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford) , Ricardo A Fernandes (Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford) , Kristina A Ganzinger (Department of Chemistry, University of Cambridge) , Steven F Lee (Department of Chemistry, University of Cambridge) , Christian Siebold (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , James Mccoll (Department of Chemistry, University of Cambridge) , Peter Jönsson (Department of Chemistry, University of Cambridge) , Matthieu Palayret (Department of Chemistry, University of Cambridge) , Karl Harlos (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Charlotte H Coles (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Edith Jones (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Yuan Lui (Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford) , Elizabeth Huang (Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford) , Robert J C Gilbert (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , David Klenerman (Department of Chemistry, University of Cambridge) , A Radu Aricescu (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Simon J Davis (Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Immunology

State: Published (Approved)
Published: March 2016

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.

Journal Keywords: Signal transduction; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)