3fc0

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1.8 A crystal structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells1.8 A crystal structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells

Structural highlights

3fc0 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.76Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TNF18_MOUSE Cytokine that binds to TNFRSF18/AITR/GITR (PubMed:14521928, PubMed:14647196). Regulates T-cell responses (PubMed:14647196). Can function as costimulator and lower the threshold for T-cell activation and T-cell proliferation (PubMed:14608036, PubMed:15128759). Important for interactions between activated T-lymphocytes and endothelial cells. Mediates activation of NF-kappa-B (PubMed:14521928, PubMed:14647196, PubMed:18178614). Triggers increased phosphorylation of STAT1 and up-regulates expression of VCAM1 and ICAM1 (By similarity). Promotes leukocyte adhesion to endothelial cells (PubMed:23892569). Regulates migration of monocytes from the splenic reservoir to sites of inflammation (PubMed:24107315).[UniProtKB:Q9UNG2][1] [2] [3] [4] [5] [6] [7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Glucocorticoid-induced TNF receptor ligand (GITRL), a prominent member of the TNF superfamily, activates its receptor on both effector and regulatory T cells to generate critical costimulatory signals that have been implicated in a wide range of T-cell immune functions. The crystal structures of murine and human orthologs of GITRL recombinantly expressed in Escherichia coli have previously been determined. In contrast to all classical TNF structures, including the human GITRL structure, murine GITRL demonstrated a unique ;strand-exchanged' dimeric organization. Such a novel assembly behavior indicated a dramatic impact on receptor activation as well as on the signaling mechanism associated with the murine GITRL costimulatory system. In this present work, the 1.8 A resolution crystal structure of murine GITRL expressed in Drosophila melanogaster S2 cells is reported. The eukaryotic protein-expression system allows transport of the recombinant protein into the extracellular culture medium, thus maximizing the possibility of obtaining correctly folded material devoid of any folding/assembly artifacts that are often suspected with E. coli-expressed proteins. The S2 cell-expressed murine GITRL adopts an identical ;strand-exchanged' dimeric structure to that observed for the E. coli-expressed protein, thus conclusively demonstrating the novel quaternary structure assembly behavior of murine GITRL.

1.8 A structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells.,Chattopadhyay K, Ramagopal UA, Nathenson SG, Almo SC Acta Crystallogr D Biol Crystallogr. 2009 May;65(Pt 5):434-9. Epub 2009, Apr 18. PMID:19390148[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Yu KY, Kim HS, Song SY, Min SS, Jeong JJ, Youn BS. Identification of a ligand for glucocorticoid-induced tumor necrosis factor receptor constitutively expressed in dendritic cells. Biochem Biophys Res Commun. 2003 Oct 17;310(2):433-8. PMID:14521928
  2. ↑ Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15059-64. Epub 2003 Nov 7. PMID:14608036 doi:http://dx.doi.org/10.1073/pnas.2334901100
  3. ↑ Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, Youn BS, Vinay DS, Kwon BS. Cloning and characterization of GITR ligand. Genes Immun. 2003 Dec;4(8):564-9. PMID:14647196 doi:http://dx.doi.org/10.1038/sj.gene.6364026
  4. ↑ Ji HB, Liao G, Faubion WA, Abadia-Molina AC, Cozzo C, Laroux FS, Caton A, Terhorst C. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol. 2004 May 15;172(10):5823-7. PMID:15128759
  5. ↑ Zhou Z, Tone Y, Song X, Furuuchi K, Lear JD, Waldmann H, Tone M, Greene MI, Murali R. Structural basis for ligand-mediated mouse GITR activation. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):641-5. Epub 2008 Jan 4. PMID:18178614
  6. ↑ Lacal PM, Petrillo MG, Ruffini F, Muzi A, Bianchini R, Ronchetti S, Migliorati G, Riccardi C, Graziani G, Nocentini G. Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion. J Pharmacol Exp Ther. 2013 Oct;347(1):164-72. doi: 10.1124/jpet.113.207605. Epub , 2013 Jul 26. PMID:23892569 doi:http://dx.doi.org/10.1124/jpet.113.207605
  7. ↑ Liao G, van Driel B, Magelky E, O'Keeffe MS, de Waal Malefyt R, Engel P, Herzog RW, Mizoguchi E, Bhan AK, Terhorst C. Glucocorticoid-induced TNF receptor family-related protein ligand regulates the migration of monocytes to the inflamed intestine. FASEB J. 2014 Jan;28(1):474-84. doi: 10.1096/fj.13-236505. Epub 2013 Oct 9. PMID:24107315 doi:http://dx.doi.org/10.1096/fj.13-236505
  8. ↑ Chattopadhyay K, Ramagopal UA, Nathenson SG, Almo SC. 1.8 A structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells. Acta Crystallogr D Biol Crystallogr. 2009 May;65(Pt 5):434-9. Epub 2009, Apr 18. PMID:19390148 doi:10.1107/S0907444909005721

3fc0, resolution 1.76Å

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