The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis

Ting, Yi Tian, Petersen, Jan, Ramarathinam, Sri H., Scally, Stephen W., Loh, Khai L., Thomas, Ranjeny, Suri, Anish, Baker, Daniel G., Purcell, Anthony W., Reid, Hugh H. and Rossjohn, Jamie (2018) The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis. The Journal of Biological Chemistry, 293 9: 3236-3251. doi:10.1074/jbc.RA117.001013


Author Ting, Yi Tian
Petersen, Jan
Ramarathinam, Sri H.
Scally, Stephen W.
Loh, Khai L.
Thomas, Ranjeny
Suri, Anish
Baker, Daniel G.
Purcell, Anthony W.
Reid, Hugh H.
Rossjohn, Jamie
Title The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
0021-9258
1067-8816
Publication date 2018-01-09
Year available 2018
Sub-type Article (original research)
DOI 10.1074/jbc.RA117.001013
Open Access Status PMC
Volume 293
Issue 9
Start page 3236
End page 3251
Total pages 16
Place of publication Rockville, MD United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract Thelocus is strongly associated with rheumatoid arthritis (RA) susceptibility, whereupon citrullinated self-peptides bind to HLA-DR molecules bearing the shared epitope (SE) amino acid motif. However, the differing propensity for citrullinated/non-citrullinated self-peptides to bind given HLA-DR allomorphs remains unclear. Here, we used a fluorescence polarization assay to determine a hierarchy of binding affinities of 34 self-peptides implicated in RA against three HLA-DRB1 allomorphs (HLA-DRB1*04:01/*04:04/*04:05) each possessing the SE motif. For all three HLA-DRB1 allomorphs, we observed a strong correlation between binding affinity and citrullination at P4 of the bound peptide ligand. A differing hierarchy of peptide-binding affinities across the three HLA-DRB1 allomorphs was attributable to the β-chain polymorphisms that resided outside the SE motif and were consistent with sequences of naturally presented peptide ligands. Structural determination of eight HLA-DR4-self-epitope complexes revealed strict conformational convergence of the P4-Cit and surrounding HLA β-chain residues. Polymorphic residues that form part of the P1 and P9 pockets of the HLA-DR molecules provided a structural basis for the preferential binding of the citrullinated self-peptides to the HLA-DR4 allomorphs. Collectively, we provide a molecular basis for the interplay between citrullination of self-antigens and HLA polymorphisms that shape peptide-HLA-DR4 binding affinities in RA.
Keyword X-ray crystallography
arthritis
major histocompatibility complex (MHC)
mass spectrometry (MS)
structural biology
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 07 Mar 2018, 11:54:13 EST