Influence of histidine beta81 of HLA-DR101 on peptide binding and presentation to T-cell receptor.
HA(306-318) is an immunodominant peptide of the hemagglutinin of influenza virus that binds to most human leukocyte antigen (HLA-DR) alleles, while p18(73-85) is a HIV peptide characterized as a DR101 binding peptide. Our results demonstrate that crystal relaxation leads to the loss of a hydrogen bond between the beta81 histidine and the HA(306-318) peptide. This histidine is also involved in the binding of superantigens like SEA via a coordination of a zinc atom. To monitor the interaction of these peptides with this histidine of HLA-DR molecules, chemical modification, peptide binding on HLA-DR101 wild type and mutated molecules, and proliferation experiments were conducted, together with molecular simulation of HLA-DR/peptide molecular complexes. Our data suggest a different binding peptide pattern, depending of whether the peptide is HLA-DR101 allele specific or a shared one. Furthermore, tyrosine substitution at position beta81 does not affect either peptide binding or HA(306-318) clone-specific T-cell proliferation. On the contrary, the alanine substitution at position HLA-DR101 beta81 abrogated both peptide binding and T-cell proliferation. These results suggest that the histidine 81 on the DRbeta chain plays an important role in the HLA-DR peptide binding, more likely by polar interactions of the amino acid side chain ring with the peptide.
Figueredo Dos Santos
Creusioni
C
University of Paraiba, Recife, Brazil.
Tilkin-Mariame
Anne Françoise
AF
De Préval
Claude
C
Lakhdar-Ghazal
Faouzi
F
D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D002478:Cells, Cultured; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006639:Histidine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000145:classification / Q000378:metabolism
D006684:HLA-DR Antigens; C469715:HLA-DR101 antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D006639:Histidine