The functional significance of two amino acid polymorphisms in the antigen-presenting domain of class I MHC molecules. Molecular dissection of K(bm3 1)

J. K. Pullen, H. D. Hunt, R. M. Horton, Larry R Pease

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Abstract

The functional properties of two amino acid substitutions, characteristic of the bm3 mutation, in the Kb class I glycoprotein were analyzed in light of the HLA-A2 crystal model. The model predicts that amino acid residues extending into the proposed ligand-binding site or projecting up from the α-helices are functional with respect to peptide Ag presentation; whereas those residues pointing away from the site are silent. L cell clones expressing Kb, K(bm3), and derivatives of K(bm3), K(bm3-77) (Asp → Ser 'ligand-binding') and K(bm3-89) (Lys → Ala 'silent'), were generated for the analysis. Serologic characterization of this panel of cells by using the mAb B8-24-3, EH-144, 20-8-4, K9-136, and Y-25 (Kb but not K(bm3) specific) revealed the loss of the epitopes recognized by these mAb in the K(bm3-89) clone and the retention of these epitopes in the K(bm3-77) clone. Analysis of the L cell clones by using B6 anti-bm3 CTL demonstrated that L cell clones expressing K(bm3) or K(bm3-77) were lysed by these CTL, whereas clones expressing Kb, K(bm3-89), and L(d) were not lysed. In reciprocal experiments, bm3 anti-B6 CTL lysed L cell clones expressing Kb or K(bm3-89) but were unable to lyse clones expressing K(bm3), K(bm3-77), and L(d). The results indicate that the substitution at amino acid 89 determines the K(bm3) serologic phenotype, whereas the K(bm3) alloreactive phenotype is primarily determined by the substitution at amino acid 77. These findings are in good agreement with the predictions derived from the x-ray crystal model of the HLA-A2 molecule.

Original languageEnglish (US)
Pages (from-to)1674-1679
Number of pages6
JournalJournal of Immunology
Volume143
Issue number5
StatePublished - 1989

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ASJC Scopus subject areas

  • Immunology

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