title: Molecular architecture of the αβ T cell receptor-CD3 complex.
abstract: αβ T-cell receptor (TCR) activation plays a crucial role for T-cell function. However, the TCR itself does not possess signaling domains. Instead, the TCR is noncovalently coupled to a conserved multisubunit signaling apparatus, the CD3 complex, that comprises the CD3εγ, CD3εδ, and CD3ζζ dimers. How antigen ligation by the TCR triggers CD3 activation and what structural role the CD3 extracellular domains (ECDs) play in the assembled TCR-CD3 complex remain unclear. Here, we use two complementary structural approaches to gain insight into the overall organization of the TCR-CD3 complex. Small-angle X-ray scattering of the soluble TCR-CD3εδ complex reveals the CD3εδ ECDs to sit underneath the TCR α-chain. The observed arrangement is consistent with EM images of the entire TCR-CD3 integral membrane complex, in which the CD3εδ and CD3εγ subunits were situated underneath the TCR α-chain and TCR β-chain, respectively. Interestingly, the TCR-CD3 transmembrane complex bound to peptide-MHC is a dimer in which two TCRs project outward from a central core composed of the CD3 ECDs and the TCR and CD3 transmembrane domains. This arrangement suggests a potential ligand-dependent dimerization mechanism for TCR signaling. Collectively, our data advance our understanding of the molecular organization of the TCR-CD3 complex, and provides a conceptual framework for the TCR activation mechanism.
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305; Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Michael E
authors.initials: ME
authors.lastname: Birnbaum
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Richard
authors.initials: R
authors.lastname: Berry
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Hsiao
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Shingu-Vazquez
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yu
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Deepa
authors.initials: D
authors.lastname: Waghray
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; jamie.rossjohn@monash.edu twalz@hms.harvard.edu kcgarcia@stanford.edu.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115; The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; and jamie.rossjohn@monash.edu twalz@hms.harvard.edu kcgarcia@stanford.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305; Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305 jamie.rossjohn@monash.edu twalz@hms.harvard.edu kcgarcia@stanford.edu.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D020816:Amino Acid Motifs; D000941:Antigens / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008854:Microscopy, Electron; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry; D012542:Scattering, Radiation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000737:chemistry; D014965:X-Rays
chemical_list: D000941:Antigens; D008024:Ligands; D010455:Peptides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: T-cell receptor; electron microscopy; small-angle X-ray scattering