The Role of Amino Acid Position and Side Chain Structure in Serological and CTL-Defined Epitopes on the HLA-A2.1 Molecule
A major focus of current immunological research is to determine the structure-function relationships of class I MHC molecules. The determination of the three-dimensional structure of HLA-A2.1 by Bjorkman et al. (1987a, 1987b) has significantly advanced our ability to achieve this goal. The α3 domain, which composes the membrane proximal region of the molecule, has a structure similar to that of the constant region of immunoglobulin, and primarily associates with β2- microglobulin. The membrane distal region consists of the α1 and α2 domains which interact to form a β-sheet platform, on top of which reside two antiparallel α-helices that are separated by a long groove. It was hypothesized that this groove acts as the binding site for peptides that are recognized by the TCR in association with class I molecules and in fact, an unidentified peptide(s) was associated with this groove in the crystal structure. An analysis of the crystallographic structure of HLA-A2.1 reveals that nearly all of the side chains of the polymorphic residues are oriented such that they point into the groove of the molecule and thus could be important in mediating contact with peptide, or they point upward from the α-helices and may thus be important in interacting with the TCR (Parham et al. 1988).
KeywordsInfluenza Val152 Prefix Ferrone Bluestone
Unable to display preview. Download preview PDF.
- Cowan EP, Jelachich ML, Coligan JE, Biddison WE (1987) Site-directed mutagenesis of an HLA-A3 gene identifies amino acid 152 as crucial for major histocompatibility complex-restricted and alloreactive cytotoxic T-lymphocyte recognition. Proc Natl Acad Sci USA 84: 5014–5018PubMedCrossRefGoogle Scholar
- Hogan KT, Clayberger C, Bernhard EJ, Walk SF, Ridge JP, Parham P, Krensky AM, Engelhard VH (1988a) Identification by site-directed mutagenesis of amino acid residues contributing to serologic and CTL- defined epitope differences between HLA-A2.1 and HLA-A2.3. J Immunol 141: 2519–2525PubMedGoogle Scholar
- Vega MA, Ezquerra A, Rojo S, Aparicio P, Bragado R, Lopez de Castro JA (1985) Structural analysis of an HLA-B27 functional variant: Identification of residues that contribute to the specificity of recognition of cytolytic T lymphocytes. Proc Natl Acad Sci USA 82: 7394–7398PubMedCrossRefGoogle Scholar