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The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA

By Diana A. Pippig, Johannes C. Hellmuth, Sheng Cui, Axel Kirchhofer, Katja Lammens, Alfred Lammens, Andreas Schmidt, Simon Rothenfusser and Karl-Peter Hopfner

Abstract

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

Topics: Structural Biology
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:2665237
Provided by: PubMed Central

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Citations

  1. (2006). Intracellular pattern recognition receptors in the host response.
  2. (2006). Pathogen recognition and innate immunity.

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