The critical role of a solvent-exposed residue of an MHC class I-restricted peptide in MHC-peptide binding

International Immunology
R HuardJ Nikolić-Zugić

Abstract

The immunodominant ovalbumin257-264 (OVA-8, SIINFEKL) and herpes simplex virus gB496-503 (HSV-8, SSIEFARL) peptides share 50% amino acid identity (residues P1, P3, P5 and P8) and bind with comparable efficacy to the murine MHC-encoded class I molecule H-2Kb. However, these two peptides bind differently to H-2Kbm8, a natural H-2Kb variant with a substitution in four amino acids on the floor of the peptide-binding site; HSV-8 binds with high and OVA-8 with a relatively low efficacy. To investigate which of the non-homologous peptide residues were responsible for this differential binding, we used substituted peptide variants and the class I thermodynamic stabilization assay. Variation at the solvent-exposed peptide residues P6 and P7 did not appreciably influence binding. By contrast, variation at the buried P2 and, surprisingly, at the solvent-exposed P4 residue was found to be important. Transplantation of the HSV-8 P2 or P4 residues onto the OVA-8 backbone created variant peptides O2S (P2I-->S) and O4E (P4N-->E) that bound considerably better to H-2Kbm8 than OVA-8. Furthermore, the double-substituted peptide, O2S4E, bound even better, revealing a cooperative effect of the two residues. The reciprocally substituted peptides H2I...Continue Reading

Citations

Nov 17, 2010·Journal of Molecular Modeling·Athanassios StavrakoudisVasso Apostolopoulos
Apr 28, 2004·Microbes and Infection·Janko Nikolich-ZugichIlhem Messaoudi
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