Structural basis of assembly of the human T cell receptor-CD3 complex

Nature. 2019 Sep;573(7775):546-552. doi: 10.1038/s41586-019-1537-0. Epub 2019 Aug 28.

Abstract

The αβ T cell receptor (TCR), in association with the CD3γε-CD3δε-CD3ζζ signalling hexamer, is the primary determinant of T cell development and activation, and of immune responses to foreign antigens. The mechanism of assembly of the TCR-CD3 complex remains unknown. Here we report a cryo-electron microscopy structure of human TCRαβ in complex with the CD3 hexamer at 3.7 Å resolution. The structure contains the complete extracellular domains and all the transmembrane helices of TCR-CD3. The octameric TCR-CD3 complex is assembled with 1:1:1:1 stoichiometry of TCRαβ:CD3γε:CD3δε:CD3ζζ. Assembly of the extracellular domains of TCR-CD3 is mediated by the constant domains and connecting peptides of TCRαβ that pack against CD3γε-CD3δε, forming a trimer-like structure proximal to the plasma membrane. The transmembrane segment of the CD3 complex adopts a barrel-like structure formed by interaction of the two transmembrane helices of CD3ζζ with those of CD3γε and CD3δε. Insertion of the transmembrane helices of TCRαβ into the barrel-like structure via both hydrophobic and ionic interactions results in transmembrane assembly of the TCR-CD3 complex. Together, our data reveal the structural basis for TCR-CD3 complex assembly, providing clues to TCR triggering and a foundation for rational design of immunotherapies that target the complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular*
  • Protein Domains
  • Protein Structure, Quaternary
  • Receptor-CD3 Complex, Antigen, T-Cell / chemistry*
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism

Substances

  • Receptor-CD3 Complex, Antigen, T-Cell