4qi2

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X-ray structure of the ROQ domain from murine Roquin-1 in complex with a 23-mer Tnf-CDE RNA

Structural highlights

4qi2 is a 8 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 3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RC3H1_MOUSE Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF and in many more mRNAs (PubMed:23663784). Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs. In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4/Ox40 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation.[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Roquin function in T cells is essential for the prevention of autoimmune disease. Roquin interacts with the 3' untranslated regions (UTRs) of co-stimulatory receptors and controls T-cell activation and differentiation. Here we show that the N-terminal ROQ domain from mouse roquin adopts an extended winged-helix (WH) fold, which is sufficient for binding to the constitutive decay element (CDE) in the Tnf 3' UTR. The crystal structure of the ROQ domain in complex with a prototypical CDE RNA stem-loop reveals tight recognition of the RNA stem and its triloop. Surprisingly, roquin uses mainly non-sequence-specific contacts to the RNA, thus suggesting a relaxed CDE consensus and implicating a broader spectrum of target mRNAs than previously anticipated. Consistently with this, NMR and binding experiments with CDE-like stem-loops together with cell-based assays confirm roquin-dependent regulation of relaxed CDE consensus motifs in natural 3' UTRs.

Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation.,Schlundt A, Heinz GA, Janowski R, Geerlof A, Stehle R, Heissmeyer V, Niessing D, Sattler M Nat Struct Mol Biol. 2014 Aug;21(8):671-8. doi: 10.1038/nsmb.2855. Epub 2014 Jul , 13. PMID:25026077[8]

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

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References

  1. ↑ Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI, Cornall RJ, Goodnow CC. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005 May 26;435(7041):452-8. PMID:15917799 doi:http://dx.doi.org/10.1038/nature03555
  2. ↑ Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Hutloff A, Giles KM, Leedman PJ, Lam KP, Goodnow CC, Vinuesa CG. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature. 2007 Nov 8;450(7167):299-303. doi: 10.1038/nature06253. PMID:18172933 doi:http://dx.doi.org/10.1038/nature06253
  3. ↑ Athanasopoulos V, Barker A, Yu D, Tan AH, Srivastava M, Contreras N, Wang J, Lam KP, Brown SH, Goodnow CC, Dixon NE, Leedman PJ, Saint R, Vinuesa CG. The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs. FEBS J. 2010 May;277(9):2109-27. doi: 10.1111/j.1742-4658.2010.07628.x. PMID:20412057 doi:http://dx.doi.org/10.1111/j.1742-4658.2010.07628.x
  4. ↑ Glasmacher E, Hoefig KP, Vogel KU, Rath N, Du L, Wolf C, Kremmer E, Wang X, Heissmeyer V. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol. 2010 Aug;11(8):725-33. doi: 10.1038/ni.1902. Epub 2010 Jul 18. PMID:20639877 doi:http://dx.doi.org/10.1038/ni.1902
  5. ↑ Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell. 2013 May 9;153(4):869-81. doi: 10.1016/j.cell.2013.04.016. PMID:23663784 doi:http://dx.doi.org/10.1016/j.cell.2013.04.016
  6. ↑ Vogel KU, Edelmann SL, Jeltsch KM, Bertossi A, Heger K, Heinz GA, Zoller J, Warth SC, Hoefig KP, Lohs C, Neff F, Kremmer E, Schick J, Repsilber D, Geerlof A, Blum H, Wurst W, Heikenwalder M, Schmidt-Supprian M, Heissmeyer V. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity. 2013 Apr 18;38(4):655-68. doi: 10.1016/j.immuni.2012.12.004. Epub 2013 , Apr 11. PMID:23583643 doi:http://dx.doi.org/10.1016/j.immuni.2012.12.004
  7. ↑ Pratama A, Ramiscal RR, Silva DG, Das SK, Athanasopoulos V, Fitch J, Botelho NK, Chang PP, Hu X, Hogan JJ, Mana P, Bernal D, Korner H, Yu D, Goodnow CC, Cook MC, Vinuesa CG. Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity. 2013 Apr 18;38(4):669-80. doi: 10.1016/j.immuni.2013.01.011. Epub 2013 , Apr 11. PMID:23583642 doi:http://dx.doi.org/10.1016/j.immuni.2013.01.011
  8. ↑ Schlundt A, Heinz GA, Janowski R, Geerlof A, Stehle R, Heissmeyer V, Niessing D, Sattler M. Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. Nat Struct Mol Biol. 2014 Aug;21(8):671-8. doi: 10.1038/nsmb.2855. Epub 2014 Jul , 13. PMID:25026077 doi:http://dx.doi.org/10.1038/nsmb.2855

Contents


PDB ID 4qi2

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