title: Initiation of T cell signaling by CD45 segregation at 'close contacts'.
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.
authors.affiliation: Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Veronica T
authors.initials: VT
authors.lastname: Chang
authors.affiliation: Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Fernandes
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Ganzinger
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Lee
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: James
authors.initials: J
authors.lastname: McColl
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: Peter
authors.initials: P
authors.lastname: Jönsson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Palayret
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Coles
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.affiliation: Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lui
authors.affiliation: Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Huang
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: Robert J C
authors.initials: RJC
authors.lastname: Gilbert
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW.
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN.
authors.forename: A Radu
authors.initials: AR
authors.lastname: Aricescu
authors.affiliation: Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
mesh_terms: D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence / Q000379:methods; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human