5nig

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Crystal structure of HLA-DRB1*04:01 with modified alpha-enolase peptide 326-340 (arginine 327 to citrulline)

Structural highlights

5nig is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.35Å
Ligands:CIR, MPD, PGE, URE
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ENOA_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 PubMed

ACPA-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.

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Citations
9 reviews cite this structure
PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets.
Curran et al. (2020)
8 more
15 other articles
No citations found

See Also

References

  1. ↑ Ray R, Miller DM. Cloning and characterization of a human c-myc promoter-binding protein. Mol Cell Biol. 1991 Apr;11(4):2154-61. PMID:2005901
  2. ↑ Sugahara T, Nakajima H, Shirahata S, Murakami H. Purification and characterization of immunoglobulin production stimulating factor-II beta derived from Namalwa cells. Cytotechnology. 1992;10(2):137-46. PMID:1369209
  3. ↑ Ghosh AK, Steele R, Ray RB. Functional domains of c-myc promoter binding protein 1 involved in transcriptional repression and cell growth regulation. Mol Cell Biol. 1999 Apr;19(4):2880-6. PMID:10082554
  4. ↑ Feo S, Arcuri D, Piddini E, Passantino R, Giallongo A. ENO1 gene product binds to the c-myc promoter and acts as a transcriptional repressor: relationship with Myc promoter-binding protein 1 (MBP-1). FEBS Lett. 2000 May 4;473(1):47-52. PMID:10802057
  5. ↑ Lopez-Alemany R, Longstaff C, Hawley S, Mirshahi M, Fabregas P, Jardi M, Merton E, Miles LA, Felez J. Inhibition of cell surface mediated plasminogen activation by a monoclonal antibody against alpha-Enolase. Am J Hematol. 2003 Apr;72(4):234-42. PMID:12666133 doi:http://dx.doi.org/10.1002/ajh.10299
  6. ↑ Ray R, Miller DM. Cloning and characterization of a human c-myc promoter-binding protein. Mol Cell Biol. 1991 Apr;11(4):2154-61. PMID:2005901
  7. ↑ Sugahara T, Nakajima H, Shirahata S, Murakami H. Purification and characterization of immunoglobulin production stimulating factor-II beta derived from Namalwa cells. Cytotechnology. 1992;10(2):137-46. PMID:1369209
  8. ↑ Ghosh AK, Steele R, Ray RB. Functional domains of c-myc promoter binding protein 1 involved in transcriptional repression and cell growth regulation. Mol Cell Biol. 1999 Apr;19(4):2880-6. PMID:10082554
  9. ↑ Feo S, Arcuri D, Piddini E, Passantino R, Giallongo A. ENO1 gene product binds to the c-myc promoter and acts as a transcriptional repressor: relationship with Myc promoter-binding protein 1 (MBP-1). FEBS Lett. 2000 May 4;473(1):47-52. PMID:10802057
  10. ↑ Lopez-Alemany R, Longstaff C, Hawley S, Mirshahi M, Fabregas P, Jardi M, Merton E, Miles LA, Felez J. Inhibition of cell surface mediated plasminogen activation by a monoclonal antibody against alpha-Enolase. Am J Hematol. 2003 Apr;72(4):234-42. PMID:12666133 doi:http://dx.doi.org/10.1002/ajh.10299
  11. ↑ 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. Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint. J Autoimmun. 2018 May 28. pii: S0896-8411(18)30128-8. doi:, 10.1016/j.jaut.2018.04.004. PMID:29853344 doi:http://dx.doi.org/10.1016/j.jaut.2018.04.004

Contents


PDB ID 5nig

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