Natural peptide ligand motifs of two HLA molecules associated with myasthenia gravis.
The peptide motifs of two HLA molecules, B8 and DR3(17), which are associated with autoimmune diseases including myasthenia gravis, were determined from natural peptide pools using Edman degradation. The majority of HLA-B8 ligands are nonamers preferentially terminated by leucine. As a characteristic feature of the HLA-B8 motif, there is a high degree of conservation of positively charged amino acids at position 3 and 5, exclusively lysine at position 3, and lysine or arginine at position 5. Additional evidence for this allele-specific motif is the presence of these features in several viral peptides recognized by HLA-B8 restricted T cells. The DR3(17) motif is characterized by four conserved anchor-like positions ordered in an almost symmetrical arrangement, as has been found for DR1 and DR5 motifs. A first hydrophobic/aromatic anchor three to four residues apart from the N-terminus (at relative position 1) appears to be a common feature of DR ligands. The second anchor is an aspartate at relative position 4, which is likely to be the DR3(17)-specific contact site in the groove. Two additional conserved positions closer to the C-terminus are occupied by charged amino acids at relative position 6 and by hydrophobic/aromatic residues at positions 8, 9, or 10. Eight individual naturally processed DR17 ligands were sequenced and were found to be derived from exogenous proteins and cytoplasmic membrane receptors. These natural peptides conform well to the determined motif. A single exchange of the anchor-like positions in a model peptide abrogated binding to DR17+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Malcherek
G
G
Neurologische Klinik, Universität Tübingen, Germany.
Falk
K
K
Rötzschke
O
O
Rammensee
H G
HG
Stevanović
S
S
Gnau
V
V
Jung
G
G
Melms
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015795:HLA-B8 Antigen / Q000378:metabolism*; D015803:HLA-DR3 Antigen / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010455:Peptides / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000276:immunology; D016415:Sequence Alignment
D015795:HLA-B8 Antigen; D015803:HLA-DR3 Antigen; D008024:Ligands; D010455:Peptides; D011950:Receptors, Cholinergic