Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases

• Published in: The Journal of experimental medicine Vol. 181; no. 5; pp. 1597 - 1601
• Main Authors: Wucherpfennig, K W, Strominger, J L
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 01.05.1995
• Subjects: Amino Acid Sequence; Autoimmune Diseases - etiology; Autoimmune Diseases - genetics; Genes, MHC Class II; HLA-DQ Antigens - genetics; HLA-DQ Antigens - metabolism; HLA-DR Antigens - genetics; HLA-DR Antigens - metabolism; Humans; Molecular Sequence Data; Peptide Fragments - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.181.5.1597

The peptide-binding site of human HLA-DR molecules is generated by the first domains of the conserved DR alpha and the polymorphic DR beta chain. A prominent hydrophobic pocket that is highly conserved between human DR molecules accommodates the primary anchor residue. Most residues that shape this pocket are from the DR alpha chain; however, the size of this pocket is controlled by the Val/Gly dimorphism at position 86 of the DR beta chain. When glycine is present at DR beta 86, aliphatic or aromatic residues can anchor the peptide; with valine at DR beta 86, the pocket is smaller so that tyrosine and tryptophan cannot be accommodated. In the HLA-DR1 structure, shallower pockets accommodate other peptide side chains, particularly side chains of P4, P6, P7, and P9 (relative to the first anchor P1). Peptide residues at these positions appear to contribute to the specificity of peptide binding to different DR molecules.