H-2Dd exploits a four residue peptide binding motif.
We have characterized the amino acid sequences of over 20 endogenous peptides bound by a soluble analog of H-2Dd, H-2Dds. Synthetic analogs corresponding to self, viral, tumor, or motif peptides were then tested for their ability to bind to H-2Dd by serologic epitope induction assays using both purified soluble protein and cell surface H-2Dd. The dominant primary sequence motif included glycine at position 2, proline at position 3, and a hydrophobic COOH terminus: leucine, isoleucine, or phenylalanine at position 9 or 10. Ancillary support for high affinity binding was contributed by a positively charged residue at position 5. Three-dimensional computer models of H-2Dds/peptide complexes, based on the crystallographic structure of the human HLA-B27/peptide complex, showed that the basic residue at position 5 was in position to form a salt bridge with aspartic acid at position 156, a polymorphic residue of the H-2Dd heavy (H) chain. Analysis of 28 such models, including 17 based on nonamer self-peptides, revealed considerable variation in the structure of the major histocompatibility complex (MHC) surrounding peptide residue 1, depending on the size and charge of the side chain. Interactions between the side chains of peptide residues 5 and 7, and 6 and 8 commonly occurred. Those peptide positions with limited sequence variability and least solvent accessibility may satisfy structural requirements for high affinity binding of the peptide to the MHC class I H chain, whereas the highly variable positions of the peptide (such as positions 4, 6, and 8) may contribute more to the T cell epitopes.
Corr
M
M
Molecular Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Boyd
L F
LF
Padlan
E A
EA
Margulies
D H
DH
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000378:metabolism*; D015488:HIV Antigens / Q000737:chemistry; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D001324:Autoantigens; D006183:H-2 Antigens; D015488:HIV Antigens; D008024:Ligands; D010455:Peptides