A post‐translational modification of nuclear proteins, N G ,N G ‐dimethyl‐Arg, found in a natural HLA class I peptide ligand

Abstract

Presentation of peptides derived from endogenous proteins by class I major histocompatibility complex molecules is essential both for immunological self‐tolerance and induction of cytotoxic T‐cell responses against intracellular parasites. Despite frequent and diverse post‐translational modification of eukaryotic cell proteins, very few class I‐bound peptides with post‐translationally modified residues are known. Here we describe a natural dodecamer ligand of HLA‐B39 (B * 3910) derived from an RNA‐binding nucleoprotein that carried N G ,N G ‐dimethyl‐Arg. Although common among RNA‐binding proteins, this modification was not previously known among natural class I ligands. The sequence of this peptide was determined by Edman degradation and electrospray ion trap mass spectrometry. The fragmentation pattern of the dimethyl‐Arg side chain observed with this latter technique allowed us to unambiguously assign the isomeric form of the modified residue. The post‐translationally modified ligand was a prominent component (1–2%) of the B*3910‐bound peptide repertoire. The dimethyl‐Arg residue was located in a central position of the peptide, amenable to interacting with T‐cell receptors, and most other residues in the middle region of the peptide were Gly. These structural features strongly suggest that the post‐translationally modified residue may have a major influence on the antigenic properties of this natural ligand.