Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling

Abstract

The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD3epsilon and zeta chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD3epsilon tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement.

Figure 1.

TCR structures with different classes of ligands show distinct binding solutions. (A–C). The docking topologies are compared for the αβTCR A6 bound to a peptide-MHC class I complex (HLA-A2 with Tax P6A peptide; PDB entry 1QRN) (A), the αβTCR NKT15 bound to the complex of CD1d and the glycolipid α-galactosylceramide (PDB entry 2PO6) (B), and the γδTCR G8 bound to the nonclassical MHC class Ib molecule T22 (PDB entry 1YPZ) (C). (D–F) The placement of the TCR loops is compared for the same complexes. (D) The A6 TCR uses all six loops to contact the MHC molecule and the bound peptide. The four germline-encoded loops (α1, α2, β1, and β2) contribute to MHC binding, while the two CDR3 loops are positioned over the peptide (α3 and β3). (E) The NKT15 TCR contacts the CD1d-bound glycolipid only through germline elements encoded in the invariant TCRα chain (α1 and α3 loops). (F) The γδ TCR G8 inserts the CDR3δ chain loop into the hydrophobic groove of T22; other TCR loops do not appear to be essential for T22 binding.

Figure 2.

Conserved helical residues of MHC class I and class II proteins are often contacted by CDR1 and CDR2 residues of TCRs. Conserved MHC helical residues are highlighted in green for structures of H-2K^b (A) and I-A^b (B). The BM3.3 TCR (H-2K^b; PDB entry 1NAM) and the B3K506 TCR (I-A^b; PDB entry 3C5Z) contact these conserved helical MHC residues. TCR CDR1β and CDR2β are colored red, CDR3α and CDR3β orange, and CDR1α and CDR2α blue. Peptide residues are colored yellow. Colored cyan are the H2-K^b α1 and IA^b α1 domains, and magenta H2-K^b α2 and IA^b β1 domains.

Figure 3.

Assembly of the TCR-CD3 complex. (A) The TCR-CD3 complex is composed of four dimeric modules: TCRαβ (or γδ), CD3δε, CD3γε, and ζζ, which associate through intramembrane contacts to form the intact complex. Each dimeric signaling module associates with the TCR through a pair of acidic TM residues that bind a specific basic TM residue in the TCR. The result is an octameric complex with the stoichiometry as shown. Ribbon structures were generated from PDB entries 1MI5 (LC13 αβTCR), 1XMW (CD3δε), and 1SY6 (CD3γε). (B) NMR structure of the ζζ TM homodimer in detergent micelles (PBD entry 2HAC). The aspartic acid pair (D6-D6) that mediates assembly with TCR is located at the helix dimer interface and stabilized by interhelical H-bonds between side-chain oxygens and backbone amide protons (indicated by dotted lines). Further interface contacts include methyl and aromatic packing (such as L9-L9) and two tyrosine-threonine H-bonds (between Y12 and T17) that are critical for dimer formation.

Figure 4.

Structure of the CD3ε ITAM in the lipid-bound state. The two tyrosines (Y38 and Y49) and the two aliphatic residues (I41 and L52) of the ITAM protrude into the hydrophobic acyl chain region of the lipid bilayer. The peptide backbone of the ITAM resides primarily at the interface between the hydrated lipid headgroup region and the hydrophobic bilayer interior. The hydrophobic layer of the bilayer is shaded light blue and the hydrated lipid headgroup region in dark blue. The POPG structure graphic to the right shows the location of the hydrophilic headgroup and the hydrophobic acyl chains of the lipid (PDB entry 2K4F).