4MD4

Immune Receptor

Summary for 4MD4

• Entry DOI: 10.2210/pdb4md4/pdb
• Related: 4MCY 4MCZ 4MD0 4MD5 4MDI 4MDJ
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, Aggrecan core protein, ... (7 entities in total)
• Functional Keywords: hla-dr, antigen presentation, t-cell receptor, citrullination, membrane, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 48000.15

Authors

Scally, S.W.,Rossjohn, J. (deposition date: 2013-08-22, release date: 2013-12-04, Last modification date: 2023-11-15)

Primary citation

Scally, S.W.,Petersen, J.,Law, S.C.,Dudek, N.L.,Nel, H.J.,Loh, K.L.,Wijeyewickrema, L.C.,Eckle, S.B.,van Heemst, J.,Pike, R.N.,McCluskey, J.,Toes, R.E.,La Gruta, N.L.,Purcell, A.W.,Reid, H.H.,Thomas, R.,Rossjohn, J.
A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis.
J.Exp.Med., 210:2569-2582, 2013

PubMed Abstract: Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01(+) individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4(+) T cells in the peripheral blood of HLA-DRB1*04:01(+) RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

PubMed: 24190431
DOI: 10.1084/jem.20131241

Experimental method

X-RAY DIFFRACTION (1.95 Å)