The effect of anchor residue modifications on the stability of major histocompatibility complex class Iā€peptide interactions

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Abstract
Anchor residues in peptides determine the specificity of binding to major histocompatibility complex class I molecules through interactions of their side chains with pockets in the peptideā€binding groove. We have compared the kinetics of association of a Sendai virus nucleoproteinā€derived peptide (FAPGNYPAL, termed SV9) with Hā€2Kb class I molecules, and the same peptide iodinated on the anchor residue tyrosine (125Iā€SV9). Even though the association rates were too rapid for direct measurements, competition studies indicated that they were similar for SV9 and 125Iā€SV9. To measure the binding of nonā€radioactive SV9 directly, SV9 was tritiated (3Hā€SV9). 3Hā€SV9 remained stably associated with Hā€2Kb molecules, whereas 125Iā€SV9 dissociated in a temperatureā€dependent fashion. Thus, modifications on anchor residues do not necessarilly have to affect the specificity and association kinetics of peptide binding to class I molecules but can affect the stability of the resulting class Iā€peptide interaction. The dissociation of peptides with modified and, more generally, suboptimal anchor residue side chains may explain the presence of empty class I molecules and free class I heavy chains at the cell surface.