Arginine (Di)methylated Human Leukocyte Antigen Class I Peptides Are Favorably Presented by HLA-B*07

• DOI: 10.1021/acs.jproteome.6b00528
• Publication Date: 2016-08-09T02:47:56Z
• Authors: Fabio Marino; Geert P. M. Mommen; Anita Jeko; Hugo D. Meiring; Jacqueline A. M. ...; Richard A. Scheltema; Cécile A. C. M. v...; Albert J. R. Heck
• Keywords: 0301 basic medicine; 570; Protein-Arginine N-Methyltransferases; Proline; Gene Expression; Arginine; Methylation; Peptide Mapping; Cell Line; HLA-B7 Antigen; 03 medical and health sciences; EThcD; SDG 3 - Good Health and Well-being; Taverne; SDMA; Humans; Amino Acid Sequence; Protein Processing; Antigen Presentation; B-Lymphocytes; Binding Sites; Post-Translational; HLA class I; arginine methylation; 3. Good health; ADMA; CARD Signaling Adaptor Proteins; CARM1; Guanylate Cyclase; PRMT5; Peptides; Protein Processing, Post-Translational; Protein Binding

Alterations in protein post-translational modification (PTM) are recognized hallmarks of diseases. These modifications potentially provide a unique source of disease-related human leukocyte antigen (HLA) class I-presented peptides that can elicit specific immune responses. While phosphorylated HLA peptides have already received attention, arginine methylated HLA class I peptide presentation has not been characterized in detail. In a human B-cell line we detected 149 HLA class I peptides harboring mono- and/or dimethylated arginine residues by mass spectrometry. A striking preference was observed in the presentation of arginine (di)methylated peptides for HLA-B*07 molecules, likely because the binding motifs of this allele resemble consensus sequences recognized by arginine methyl-transferases. Moreover, HLA-B*07-bound peptides preferentially harbored dimethylated groups at the P3 position, thus consecutively to the proline anchor residue. Such a proline-arginine sequence has been associated with the arginine methyl-transferases CARM1 and PRMT5. Making use of the specific neutral losses in fragmentation spectra, we found most of the peptides to be asymmetrically dimethylated, most likely by CARM1. These data expand our knowledge of the processing and presentation of arginine (di)methylated HLA class I peptides and demonstrate that these types of modified peptides can be presented for recognition by T-cells. HLA class I peptides with mono- and dimethylated arginine residues may therefore offer a novel target for immunotherapy.