Longer peptide can be accommodated in the MHC class I binding site by a protrusion mechanism

According to current consensus, CD8(+) T cell responses are focused upon sh ort peptide sequences (8-11 amino acids) presented by MHC class I molecules . This size restriction is thought to operate mostly at the level of peptid e-MHC class I interaction. Crystal structures have shown that the free N an d C termini of a bound peptide interact through hydrogen bonding networks t o conserved residues at either end of the class I binding site. Accordingly , it is thought that the termini are fixed and that only minor variations i n peptide size are possible through a central bulging mechanism. We find th at this consensus view is not always correct as some peptide-MHC class I in teraction will accept significant extensions. Furthermore, our results indi cate that in some cases protrusion, rather than bulging, may be the mechani sm of extension. Depending upon the particular peptide-MHC combination in q uestion, such extensions can occur at either the N or C terminus (but never both at the same time). Finally, we show that MHC and T cell in some cases can detect the identity of the extension, ie. that extensions may be part of the specificity of the T cell immune response. We suggest that such exte nsions may play a physiological role.