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Nat Struct Mol Biol. 2014 Aug;21(8):671-8. doi: 10.1038/nsmb.2855. Epub 2014 Jul 13.

Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation.

Author information

1
1] Biomolecular NMR Spectroscopy, Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany. [2] Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemie, Technische Universität München, Garching, Germany. [3].
2
1] Institute of Molecular Immunology, Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Germany. [2] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [3].
3
1] Group Intracellular Transport and RNA Biology, Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany. [2].
4
Biomolecular NMR Spectroscopy, Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
5
Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemie, Technische Universität München, Garching, Germany.
6
1] Institute of Molecular Immunology, Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Germany. [2] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany.
7
Group Intracellular Transport and RNA Biology, Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
8
1] Biomolecular NMR Spectroscopy, Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany. [2] Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemie, Technische Universität München, Garching, Germany.

Abstract

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.

PMID:
25026077
DOI:
10.1038/nsmb.2855
[Indexed for MEDLINE]

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