title: Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif.
abstract: Peptide fragments of foreign and self-proteins are of great immunologic importance as their binding to major histocompatibility complex (MHC) class I or II molecules makes an interaction with a corresponding T cell receptor possible. Recently, allele-specific peptide sequence motifs proved to be responsible for MHC binding, no matter whether self- or non-self-antigens were involved. Up to now, all investigated human class II-associated peptides were derived from foreign antigenic proteins. Therefore, we undertook sequence and binding analyses with a 16-mer self-peptide (SP3) that has been eluted from HLA-DR1. Here we demonstrate, by synthetic polyalanine-based 13-mer analogues of SP3, that two bulky hydrophobic anchor residues with relative spacing i, i + 8 are sufficient for high affinity binding. This is consistent with the hydrophobic i, i + 8 binding pattern recently found for DR-restricted T cell epitopes. Nevertheless, highly helical alanine-based design peptides with anchor spacing i, i + 9 exhibit maximal affinity, whereas replacement of alanine by helix destabilizing proline abrogates binding. Thus, a two-residue contact motif is the common minimal requirement of self- and foreign peptides for high affinity anchoring to HLA-DR1. In contrast to class I, the anchor spacing of DR1-associated peptides seems to bear some variability due to conformational diversity.
authors.affiliation: Medical Research Center, University of Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kropshofer
authors.forename: H
authors.initials: H
authors.lastname: Max
authors.forename: C A
authors.initials: CA
authors.lastname: Müller
authors.forename: F
authors.initials: F
authors.lastname: Hesse
authors.forename: S
authors.initials: S
authors.lastname: Stevanovic
authors.forename: G
authors.initials: G
authors.lastname: Jung
authors.forename: H
authors.initials: H
authors.lastname: Kalbacher
mesh_terms: D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D000939:Epitopes / Q000032:analysis; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008285:Major Histocompatibility Complex; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000939:Epitopes; D015798:HLA-DR1 Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell