Structural aspects of the interaction between heterogeneic human papillomavirus type 1 E4-specific T cell receptors and the same peptide/HLA-DQ8 complex.
TCR usage has been studied in a panel of Th cell clones specific for the same peptide epitope (P N S Q D R G R P R R S D), derived from the human papillomavirus type 1 (HPV1) E4 protein, and restricted through HLA-DQ8. After identifying the V, D, and J genes used by the TCRs and sequencing across the V(D)J junctions, five different alpha-chain sequences and five different beta-chain sequences, comprising six independent clones, were identified. A structural model of our E4 peptide/HLA-DQ8 complex predicted that the guanidinyl side chain on the arginine residue at position 6 of the peptide could exist in different orientations. An intramolecular interaction between this arginine and the glutamine residue at position four appeared to control this orientation. Interacting HPV1 E4-specific TCRs would therefore have to recognize the complex in different conformations, and molecular modeling of the TCRs suggested that this could be achieved by changing the dimensions of the central pocket formed where the CDR3 loops of the TCR alpha- and beta-chains converge. It is known that interactions between bound peptide and amino acid residues lining the peptide-binding cleft of HLA molecules are important for determining the conformation and orientation of the peptide/MHC complex. The suggestion here that intramolecular interactions between amino acids of close proximity on the bound peptide are also important adds a further level of complexity to the mechanism by which TCRs interact with Ag.
Steele
J C
JC
Cancer Research Campaign Institute for Cancer Studies, The Medical School, University of Birmingham, Edgbaston, United Kingdom.
Young
S P
SP
Goodall
J C
JC
Gallimore
P H
PH
D000595:Amino Acid Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002999:Clone Cells / Q000276:immunology; D003198:Computer Simulation; D018076:DNA, Complementary / Q000235:genetics; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D018448:Models, Immunological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011487:Protein Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D018076:DNA, Complementary; D000939:Epitopes; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D046911:Macromolecular Substances; D009856:Oncogene Proteins, Viral; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C056651:oncogene protein E4, human papilloma virus type 1