Projects per year
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.
- major histocompatibility complex (MHC)
- mass spectrometry (MS)
- x-ray crystallography
- 3 Finished
Whisstock, J., Abbey, B., Nugent, K., Quiney, H. M., Godfrey, D. I., Heath, W., Fairlie, D., Chapman, H., Peele, A., Davey, J. & Wittmann, A.
30/06/14 → 31/03/21
1/01/08 → 31/12/17
Office of the Vice-Provost (Research and Research Infrastructure)
Andrew Fryga (Manager)Faculty of Medicine Nursing and Health Sciences Research Platforms
Ralf Schittenhelm (Manager)Faculty of Medicine Nursing and Health Sciences Research Platforms