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J Mol Biol. 2014 Mar 20;426(6):1351-65. doi: 10.1016/j.jmb.2013.10.040. Epub 2013 Nov 7.

RIG-I-like receptors evolved adaptively in mammals, with parallel evolution at LGP2 and RIG-I.

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Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy.
Department of Biotechnology and Biosciences, University of Milan Bicocca, 20126 Milan, Italy.
Department of Biomedical and Clinical Sciences, University of Milan, 20100 Milan, Italy.
Department of Physiopathology and Transplantation, University of Milan, 20100 Milan, Italy; Don C. Gnocchi ONLUS Foundation, IRCCS, 20100 Milan, Italy.
Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini LC, Italy. Electronic address:


RIG-I-like receptors (RLRs) are nucleic acid sensors that activate antiviral innate immune response. These molecules recognize diverse non-self RNA substrates and are antagonized by several viral inhibitors. We performed an evolutionary analysis of RLR genes (RIG-I, MDA5, and LGP2) in mammals. Results indicated that purifying selection had a dominant role in driving the evolution of RLRs. However, application of maximum-likelihood analyses identified several positions that evolved adaptively. Positively selected sites are located in all domains of MDA5 and RIG-I, whereas in LGP2 they are confined to the helicase domain. In both MDA5 and RIG-I, the linkers separating the caspase activation and recruitment domain and the helicase domain represented preferential targets of positive selection. Independent selective events in RIG-I and LGP2 targeted the corresponding site (Asp421 and Asp179, respectively) within a protruding α-helix that grips the V-shaped structure formed by the pincer. Most of the positively selected sites in MDA5 are in regions unique to this RLR, including a characteristic insertion within the helicase domain. Additional selected sites are located at the contact interface between MDA5 monomers, in spatial proximity to a positively selected human polymorphism (Arg843His) and immediately external to the parainfluenza virus 5 V protein binding region. Structural analyses suggested that the positively selected His834 residue is involved in parainfluenza virus 5 V protein binding. Data herein suggest that RLRs have been engaged in host-virus genetic conflict leading to diversifying selection and indicate parallel evolution at the same site in RIG-I and LGP2, a position likely to be of central importance in antiviral responses.


LGP2; MDA5; RIG-I; RIG-I-like receptors; positive selection

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