5nig
Crystal structure of HLA-DRB1*04:01 with modified alpha-enolase peptide 326-340 (arginine 327 to citrulline)
Structural highlights
FunctionENOA_HUMAN Multifunctional enzyme that, as well as its role in glycolysis, plays a part in various processes such as growth control, hypoxia tolerance and allergic responses. May also function in the intravascular and pericellular fibrinolytic system due to its ability to serve as a receptor and activator of plasminogen on the cell surface of several cell-types such as leukocytes and neurons. Stimulates immunoglobulin production.[1] [2] [3] [4] [5] MBP1 binds to the myc promoter and acts as a transcriptional repressor. May be a tumor suppressor.[6] [7] [8] [9] [10] Publication Abstract from PubMedACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within alpha-enolase326-340 in the context of HLA-DRB1*04:01 and assessed the corresponding CD4(+) T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated alpha-enolase326-340 peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of alpha-enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide-binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno326-340 were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno326-340 was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p=0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p=0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within alpha-enolase326-340 does not appear to lead to complete negative selection of cognate CD4(+) T cells. In RA patient samples, only T cells recognizing the citrullinated version of alpha-enolase326-340 were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance. Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint.,Pieper J, Dubnovitsky A, Gerstner C, James EA, Rieck M, Kozhukh G, Tandre K, Pellegrino S, Gebe JA, Ronnblom L, Sandalova T, Kwok WW, Klareskog L, Buckner JH, Achour A, Malmstrom V J Autoimmun. 2018 May 28. pii: S0896-8411(18)30128-8. doi:, 10.1016/j.jaut.2018.04.004. PMID:29853344[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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