| Structural highlights
6tqb is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Gene: | Rc3h1, Gm551, Kiaa2025 (LK3 transgenic mice) |
| Activity: | RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 |
| 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
Adenylate/uridylate-rich elements (AREs) are the most common cis-regulatory elements in the 3'-untranslated region (UTR) of mRNAs, where they fine-tune turnover by mediating mRNA decay. They increase plasticity and efficacy of mRNA regulation and are recognized by several ARE-specific RNA-binding proteins (RBPs). Typically, AREs are short linear motifs with a high content of complementary A and U nucleotides and often occur in multiple copies. Although thermodynamically rather unstable, the high AU-content might enable transient secondary structure formation and modify mRNA regulation by RBPs. We have recently suggested that the immunoregulatory RBP Roquin recognizes folded AREs as constitutive decay elements (CDEs), resulting in shape-specific ARE-mediated mRNA degradation. However, the structural evidence for a CDE-like recognition of AREs by Roquin is still lacking. We here present structures of CDE-like folded AREs, both in their free and protein-bound form. Moreover, the AREs in the UCP3 3'-UTR are additionally bound by the canonical ARE-binding protein AUF1 in their linear form, adopting an alternative binding-interface compared to the recognition of their CDE structure by Roquin. Strikingly, our findings thus suggest that AREs can be recognized in multiple ways, allowing control over mRNA regulation by adapting distinct conformational states, thus providing differential accessibility to regulatory RBPs.
Structural basis for the recognition of transiently structured AU-rich elements by Roquin.,Binas O, Tants JN, Peter SA, Janowski R, Davydova E, Braun J, Niessing D, Schwalbe H, Weigand JE, Schlundt A Nucleic Acids Res. 2020 Jun 3. pii: 5850806. doi: 10.1093/nar/gkaa465. PMID:32491174[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Binas O, Tants JN, Peter SA, Janowski R, Davydova E, Braun J, Niessing D, Schwalbe H, Weigand JE, Schlundt A. Structural basis for the recognition of transiently structured AU-rich elements by Roquin. Nucleic Acids Res. 2020 Jun 3. pii: 5850806. doi: 10.1093/nar/gkaa465. PMID:32491174 doi:http://dx.doi.org/10.1093/nar/gkaa465
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