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

Jesse I. Mobbs, Patricia T. Illing, Nadine L. Dudek, Andrew G. Brooks, Daniel G. Baker, Anthony W. Purcell, Jamie Rossjohn, Julian P. Vivian

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29 Citations (Scopus)


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 Band 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.

Original languageEnglish
Pages (from-to)17203-17215
Number of pages13
JournalJournal of Biological Chemistry
Issue number42
Publication statusPublished - 20 Oct 2017


  • autoimmunity
  • major histocompatibility complex (MHC)
  • mass spectrometry (MS)
  • psoriasis
  • x-ray crystallography

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