Identification of the Docking Site for CD3 on the T Cell Receptor β Chain by Solution NMR

J Biol Chem. 2015 Aug 7;290(32):19796-805. doi: 10.1074/jbc.M115.663799. Epub 2015 Jun 24.


The T cell receptor (TCR)-CD3 complex is composed of a genetically diverse αβ TCR heterodimer associated noncovalently with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates peptide-MHC recognition, whereas the CD3 molecules transduce activation signals to the T cell. Although much is known about downstream T cell signaling pathways, the mechanism whereby TCR engagement by peptide-MHC initiates signaling is poorly understood. A key to solving this problem is defining the spatial organization of the TCR-CD3 complex and the interactions between its subunits. We have applied solution NMR methods to identify the docking site for CD3 on the β chain of a human autoimmune TCR. We demonstrate a low affinity but highly specific interaction between the extracellular domains of CD3 and the TCR constant β (Cβ) domain that requires both CD3ϵγ and CD3ϵδ subunits. The mainly hydrophilic docking site, comprising 9-11 solvent-accessible Cβ residues, is relatively small (∼400 Å(2)), consistent with the weak interaction between TCR and CD3 extracellular domains, and devoid of glycosylation sites. The docking site is centered on the αA and αB helices of Cβ, which are located at the base of the TCR. This positions CD3ϵγ and CD3ϵδ between the TCR and the T cell membrane, permitting us to distinguish among several possible models of TCR-CD3 association. We further correlate structural results from NMR with mutational data on TCR-CD3 interactions from cell-based assays.

Keywords: T-cell receptor (TCR); complex; nuclear magnetic resonance (NMR); signal transduction; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • CD3 Complex / chemistry*
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Mutation
  • Protein Folding
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Subunits / chemistry*
  • Protein Subunits / genetics
  • Protein Subunits / immunology
  • Receptor-CD3 Complex, Antigen, T-Cell / chemistry*
  • Receptor-CD3 Complex, Antigen, T-Cell / genetics
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology


  • CD3 Complex
  • Protein Subunits
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Proteins

Associated data

  • PDB/3O6F
  • PDB/3TOE