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

Mobbs, Jesse I., Illing, Patricia T., Dudek, Nadine L., Brooks, Andrew G., Baker, Daniel G., Purcell, Anthony W., Rossjohn, Jamie and Vivian, Julian P. 2017. The molecular basis for peptide repertoire selection in the human leukocyte antigen (HLA) C*06:02 molecule. Journal of Biological Chemistry 292 (42) , pp. 17203-17215. 10.1074/jbc.M117.806976

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 30 July 2018
Date of Acceptance: 30 August 2017
Last Modified: 31 Jul 2018 16:28

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