Nucleic Acids Research Advance Access originally published online on February 10, 2009
Nucleic Acids Research 2009 37(6):2014-2025; doi:10.1093/nar/gkp059
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Nucleic Acids Research, 2009, Vol. 37, No. 6 2014-2025
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA
1Department of Chemistry and Biochemistry, Gene Center, 2Division of Clinical Pharmacology, Department of Internal Medicine, 3Section Gastroenterology and Endocrinology, Medizinische Klinik Innenstadt, 4Center for Integrated Protein Sciences and 5Munich Center for Advanced Photonics, Ludwig-Maximilians University Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
*To whom correspondence should be addressed. Tel: +49 0 89 2180 76953; Fax: +49 0 89 2180 76999; Email: hopfner{at}lmb.uni-muenchen.de
Received November 25, 2008. Revised January 15, 2009. Accepted January 21, 2009.
RIG-I and MDA5 sense cytoplasmic viral RNA and set-off a signal transduction cascade, leading to antiviral innate immune response. The third RIG-I-like receptor, LGP2, differentially regulates RIG-I- and MDA5-dependent RNA sensing in an unknown manner. All three receptors possess a C-terminal regulatory domain (RD), which in the case of RIG-I senses the viral pattern 5'-triphosphate RNA and activates ATP-dependent signaling by RIG-I. Here we report the 2.6 Å crystal structure of LGP2 RD along with in vitro and in vivo functional analyses and a homology model of MDA5 RD. Although LGP2 RD is structurally related to RIG-I RD, we find it rather binds double-stranded RNA (dsRNA) and this binding is independent of 5'-triphosphates. We identify conserved and receptor-specific parts of the RNA binding site. Latter are required for specific dsRNA binding by LGP2 RD and could confer pattern selectivity between RIG-I-like receptors. Our data furthermore suggest that LGP2 RD modulates RIG-I-dependent signaling via competition for dsRNA, another pattern sensed by RIG-I, while a fully functional LGP2 is required to augment MDA5-dependent signaling.
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