Structural and functional consequences of altering a peptide MHC anchor residue

J Immunol. 2001 Mar 1;166(5):3345-54. doi: 10.4049/jimmunol.166.5.3345.

Abstract

To better understand TCR discrimination of multiple ligands, we have analyzed the crystal structures of two Hb peptide/I-E(k) complexes that differ by only a single amino acid substitution at the P6 anchor position within the peptide (E73D). Detailed comparison of multiple independently determined structures at 1.9 A resolution reveals that removal of a single buried methylene group can alter a critical portion of the TCR recognition surface. Significant variance was observed in the peptide P5-P8 main chain as well as a rotamer difference at LeuP8, approximately 10 A distal from the substitution. No significant variations were observed in the conformation of the two MHC class II molecules. The ligand alteration results in two peptide/MHC complexes that generate bulk T cell responses that are distinct and essentially nonoverlapping. For the Hb-specific T cell 3.L2, substitution reduces the potency of the ligand 1000-fold. Soluble 3.L2 TCR binds the two peptide/MHC complexes with similar affinity, although with faster kinetics. These results highlight the role of subtle variations in MHC Ag presentation on T cell activation and signaling.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / immunology*
  • Animals
  • Antigen Presentation
  • Aspartic Acid / metabolism
  • Cells, Cultured
  • Crystallography, X-Ray
  • Glutamic Acid / metabolism
  • Hemoglobins / chemistry
  • Hemoglobins / immunology
  • Hemoglobins / metabolism
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism*
  • Kinetics
  • Ligands
  • Mice
  • Mice, Inbred CBA
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemical synthesis
  • Peptides / immunology*
  • Peptides / metabolism*
  • Protein Conformation
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Structure-Activity Relationship
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Hemoglobins
  • Histocompatibility Antigens Class II
  • I-E-antigen
  • Ligands
  • Peptides
  • Receptors, Antigen, T-Cell
  • Aspartic Acid
  • Glutamic Acid

Associated data

  • PDB/1FNE
  • PDB/1FNG