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Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding.
Sibener, Leah V; Fernandes, Ricardo A; Kolawole, Elizabeth M; Carbone, Catherine B; Liu, Fan; McAffee, Darren; Birnbaum, Michael E; Yang, Xinbo; Su, Laura F; Yu, Wong; Dong, Shen; Gee, Marvin H; Jude, Kevin M; Davis, Mark M; Groves, Jay T; Goddard, William A; Heath, James R; Evavold, Brian D; Vale, Ronald D; Garcia, K Christopher.
Afiliación
  • Sibener LV; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Fernandes RA; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Kolawole EM; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
  • Carbone CB; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Liu F; Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA; Institute for Systems Biology, Seattle, WA 98109, USA.
  • McAffee D; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Birnbaum ME; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Yang X; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Su LF; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Yu W; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Dong S; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Gee MH; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Jude KM; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Davis MM; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Groves JT; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Goddard WA; Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA.
  • Heath JR; Institute for Systems Biology, Seattle, WA 98109, USA.
  • Evavold BD; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
  • Vale RD; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Garcia KC; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
Cell ; 174(3): 672-687.e27, 2018 07 26.
Article en En | MEDLINE | ID: mdl-30053426
ABSTRACT
TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Activación de Linfocitos / Antígenos de Histocompatibilidad Clase I Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Activación de Linfocitos / Antígenos de Histocompatibilidad Clase I Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos