The molecular basis for peptide repertoire selection in the human leukocyte antigen (HLA) C*06:02 molecule

• DOI: 10.1074/jbc.m117.806976
• Publication Date: 2017-08-31T00:10:14Z
• Authors: Jesse I. Mobbs; Patricia T. Illing; Nadine L. Dudek; Andrew G. Brooks; Daniel G. Baker; Anthony W. Purcell; Jamie Rossjohn; Julian P. Vivian
• Keywords: Antigen Presentation; 03 medical and health sciences; ADAMTS Proteins; 0302 clinical medicine; Amino Acid Motifs; Humans; HLA-C Antigens; Peptides; Cell Line

Human leukocyte antigen (HLA)-C*06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C*06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C*06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C*06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C*06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C*06:02 possesses a deep peptide-binding groove comprising two electronegative B- and E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C*06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C*06:02.