title: Structural Model of the Extracellular Assembly of the TCR-CD3 Complex.
abstract: Antigen recognition of peptide-major histocompatibility complexes (pMHCs) by T cells, a key step in initiating adaptive immune responses, is performed by the T cell receptor (TCR) bound to CD3 heterodimers. However, the biophysical basis of the transmission of TCR-CD3 extracellular interaction into a productive intracellular signaling sequence remains incomplete. Here we used nuclear magnetic resonance (NMR) spectroscopy combined with mutational analysis and computational docking to derive a structural model of the extracellular TCR-CD3 assembly. In the inactivated state, CD3γε interacts with the helix 3 and helix 4-F strand regions of the TCR Cβ subunit, whereas CD3δε interacts with the F and C strand regions of the TCR Cα subunit in this model, placing the CD3 subunits on opposing sides of the TCR. This work identifies the molecular contacts between the TCR and CD3 subunits, identifying a physical basis for transmitting an activating signal through the complex.
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Aswin
authors.initials: A
authors.lastname: Natarajan
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Vidushan
authors.initials: V
authors.lastname: Nadarajah
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Klara
authors.initials: K
authors.lastname: Felsovalyi
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Jeyachandran
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Riley A
authors.initials: RA
authors.lastname: Wasson
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Clay
authors.initials: C
authors.lastname: Bracken
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Interdiciplinary Cooperative Melanoma Group, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: michelle.krogsgaard@nyumc.org.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
mesh_terms: D017252:CD3 Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell