Recognition of Class II MHC Peptide Ligands That Contain β-Amino Acids

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ross W ChelohaH L Ploegh

Abstract

Proteins are composed of α-amino acid residues. This consistency in backbone structure likely serves an important role in the display of an enormous diversity of peptides by class II MHC (MHC-II) products, which make contacts with main chain atoms of their peptide cargo. Peptides that contain residues with an extra carbon in the backbone (derived from β-amino acids) have biological properties that differ starkly from those of their conventional counterparts. How changes in the structure of the peptide backbone affect the loading of peptides onto MHC-II or recognition of the resulting complexes by TCRs has not been widely explored. We prepared a library of analogues of MHC-II-binding peptides derived from OVA, in which at least one α-amino acid residue was replaced with a homologous β-amino acid residue. The latter contain an extra methylene unit in the peptide backbone but retain the original side chain. We show that several of these α/β-peptides retain the ability to bind tightly to MHC-II, activate TCR signaling, and induce responses from T cells in mice. One α/β-peptide exhibited enhanced stability in the presence of an endosomal protease relative to the index peptide. Conjugation of this backbone-modified peptide to a camel...Continue Reading

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Citations

Nov 26, 2019·Chemical Communications : Chem Comm·Sebastian A AndreiLech-Gustav Milroy
Sep 2, 2020·The Journal of Biological Chemistry·Ross W ChelohaHidde L Ploegh
Apr 22, 2021·Journal of the American Chemical Society·Ruslan GibadullinSamuel H Gellman
Jun 8, 2021·Chemical Science·Attila TököliTamás A Martinek

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