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Crystal structure of HLA-DRB1*04:01 in complex with modified alpha-enolase peptide 26-40 with citrulline at the position 32
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 PubMedAntibodies 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 alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-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 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) 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. Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis.,Gerstner C, Dubnovitsky A, Sandin C, Kozhukh G, Uchtenhagen H, James EA, Ronnelid J, Ytterberg AJ, Pieper J, Reed E, Tandre C, Rieck M, Zubarev RA, Ronnblom L, Sandalova T, Buckner JH, Achour A, Malmstrom V Front Immunol. 2016 Nov 14;7:494. eCollection 2016. PMID:27895642[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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