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.
Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif.
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H Kropshofer, H Max, C A Müller, F Hesse, S Stevanovic, G Jung, H Kalbacher; Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif.. J Exp Med 1 June 1992; 175 (6): 1799–1803. doi: https://doi.org/10.1084/jem.175.6.1799
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