5JLZ

Crystal structure of HLA-DRB1*04:01 in complex with modified alpha-enolase peptide 26-40 with citrulline at the position 32

Summary for 5JLZ

• Entry DOI: 10.2210/pdb5jlz/pdb
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, Alpha-enolase, ... (5 entities in total)
• Functional Keywords: hla, autoimmune desease, rheumatoid arthritis, mhc class ii, citrulline, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01903 P13760
• Total number of polymer chains: 6
• Total formula weight: 93034.14

Authors

Dubnovitsky, A.,Kozhukh, G.,Sandalova, T.,Achour, A. (deposition date: 2016-04-28, release date: 2016-12-07, Last modification date: 2024-11-20)

Primary citation

Gerstner, C.,Dubnovitsky, A.,Sandin, C.,Kozhukh, G.,Uchtenhagen, H.,James, E.A.,Ronnelid, J.,Ytterberg, A.J.,Pieper, J.,Reed, E.,Tandre, C.,Rieck, M.,Zubarev, R.A.,Ronnblom, L.,Sandalova, T.,Buckner, J.H.,Achour, A.,Malmstrom, V.
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis.
Front Immunol, 7:494-494, 2016

PubMed Abstract: Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified α-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.

PubMed: 27895642
DOI: 10.3389/fimmu.2016.00494

Experimental method

X-RAY DIFFRACTION (1.99 Å)