Abstract:SummaryRIG-I and MDA5 sense virus-derived short 5′ppp blunt-ended or long dsRNA, respectively, causing interferon production. Non-signaling LGP2 appears to positively and negatively regulate MDA5 and RIG-I signaling, respectively. Co-crystal structures of chicken (ch) LGP2 with dsRNA display a fully or semi-closed conformation depending on the presence or absence of nucleotide. LGP2 caps blunt, 3′ or 5′ overhang dsRNA ends with 1 bp longer overall footprint than RIG-I. Structures of 1:1 and 2:1 complexes of ch… Show more
“…We observed a similar increase in the fluctuation of the RNA-binding loop in ancMDA5/LGP2a and ancMDA5/LGP2b during molecular dynamics simulations of the combined helicase + pincer + RD domains, suggesting that this observation is likely relevant to general RLR-RNA interactions and not an artifact of simulating only the RD bound to RNA (Additional file 1: Figure S6). Our results are generally consistent with recent structural studies of chicken LGP2 and MDA5, which also found the ‘RNA-binding loop’ failed to make strong contacts with RNA ligands [59]. Overall, these results suggest that the RNA-binding loop lost the capacity to bind blunt-ended and 5′ppp dsRNA ligands early in the MDA5/LGP2 lineage following the first RLR gene duplication in bilateria, and this functional shift was likely retained throughout MDA5/LGP2 evolutionary history.Fig.…”
Section: Resultssupporting
confidence: 92%
“…Our results suggest that the similarity in RNA preference between human LGP2 and RIG-I RDs originated prior to the MDA5-LGP2 duplication (in ancMDA5/LGP2b), although it did evolve from a (functionally) MDA5-like ancestor (ancMDA5/LGP2a). Our finding that human MDA5 prefers blunt-ended dsRNA over 5′ppp dsRNA is also consistent with recent analyses of chicken MDA5 [59]. …”
Section: Resultssupporting
confidence: 92%
“…Less is known about the specific RNA ligands bound by MDA5 and LGP2. LGP2 appears to bind RNA moieties similar to those of RIG-I as well as additional RNA end structures [58, 59]. The natural MDA5 ligands have remained the most mysterious, although evidence suggests that MDA5 may cooperatively bind long—and possibly short—blunt-ended dsRNA molecules or other specific virus-produced RNAs [59–61].…”
BackgroundAlthough resurrecting ancestral proteins is a powerful tool for understanding the molecular-functional evolution of gene families, nearly all studies have examined proteins functioning in relatively stable biological processes. The extent to which more dynamic systems obey the same ‘rules’ governing stable processes is unclear. Here we present the first detailed investigation of the functional evolution of the RIG-like receptors (RLRs), a family of innate immune receptors that detect viral RNA in the cytoplasm.ResultsUsing kinetic binding assays and molecular dynamics simulations of ancestral proteins, we demonstrate how a small number of adaptive protein-coding changes repeatedly shifted the RNA preference of RLRs throughout animal evolution by reorganizing the shape and electrostatic distribution across the RNA binding pocket, altering the hydrogen bond network between the RLR and its RNA target. In contrast to observations of proteins involved in metabolism and development, we find that RLR-RNA preference ‘flip flopped’ between two functional states, and shifts in RNA preference were not always coupled to gene duplications or speciation events. We demonstrate at least one reversion of RLR-RNA preference from a derived to an ancestral function through a novel structural mechanism, indicating multiple structural implementations of similar functions.ConclusionsOur results suggest a model in which frequent shifts in selection pressures imposed by an evolutionary arms race preclude the long-term functional optimization observed in stable biological systems. As a result, the evolutionary dynamics of immune receptors may be less constrained by structural epistasis and historical contingency.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0818-6) contains supplementary material, which is available to authorized users.
“…We observed a similar increase in the fluctuation of the RNA-binding loop in ancMDA5/LGP2a and ancMDA5/LGP2b during molecular dynamics simulations of the combined helicase + pincer + RD domains, suggesting that this observation is likely relevant to general RLR-RNA interactions and not an artifact of simulating only the RD bound to RNA (Additional file 1: Figure S6). Our results are generally consistent with recent structural studies of chicken LGP2 and MDA5, which also found the ‘RNA-binding loop’ failed to make strong contacts with RNA ligands [59]. Overall, these results suggest that the RNA-binding loop lost the capacity to bind blunt-ended and 5′ppp dsRNA ligands early in the MDA5/LGP2 lineage following the first RLR gene duplication in bilateria, and this functional shift was likely retained throughout MDA5/LGP2 evolutionary history.Fig.…”
Section: Resultssupporting
confidence: 92%
“…Our results suggest that the similarity in RNA preference between human LGP2 and RIG-I RDs originated prior to the MDA5-LGP2 duplication (in ancMDA5/LGP2b), although it did evolve from a (functionally) MDA5-like ancestor (ancMDA5/LGP2a). Our finding that human MDA5 prefers blunt-ended dsRNA over 5′ppp dsRNA is also consistent with recent analyses of chicken MDA5 [59]. …”
Section: Resultssupporting
confidence: 92%
“…Less is known about the specific RNA ligands bound by MDA5 and LGP2. LGP2 appears to bind RNA moieties similar to those of RIG-I as well as additional RNA end structures [58, 59]. The natural MDA5 ligands have remained the most mysterious, although evidence suggests that MDA5 may cooperatively bind long—and possibly short—blunt-ended dsRNA molecules or other specific virus-produced RNAs [59–61].…”
BackgroundAlthough resurrecting ancestral proteins is a powerful tool for understanding the molecular-functional evolution of gene families, nearly all studies have examined proteins functioning in relatively stable biological processes. The extent to which more dynamic systems obey the same ‘rules’ governing stable processes is unclear. Here we present the first detailed investigation of the functional evolution of the RIG-like receptors (RLRs), a family of innate immune receptors that detect viral RNA in the cytoplasm.ResultsUsing kinetic binding assays and molecular dynamics simulations of ancestral proteins, we demonstrate how a small number of adaptive protein-coding changes repeatedly shifted the RNA preference of RLRs throughout animal evolution by reorganizing the shape and electrostatic distribution across the RNA binding pocket, altering the hydrogen bond network between the RLR and its RNA target. In contrast to observations of proteins involved in metabolism and development, we find that RLR-RNA preference ‘flip flopped’ between two functional states, and shifts in RNA preference were not always coupled to gene duplications or speciation events. We demonstrate at least one reversion of RLR-RNA preference from a derived to an ancestral function through a novel structural mechanism, indicating multiple structural implementations of similar functions.ConclusionsOur results suggest a model in which frequent shifts in selection pressures imposed by an evolutionary arms race preclude the long-term functional optimization observed in stable biological systems. As a result, the evolutionary dynamics of immune receptors may be less constrained by structural epistasis and historical contingency.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0818-6) contains supplementary material, which is available to authorized users.
“…However, a recent study has suggested that LGP2 might also have a positive enhancement regulation mechanism for MDA5 and RIG-I. Structural analysis of LGP2 revealed that RNA-dependent binding of dsRNA by LGP2 enhanced MDA5 antiviral signaling (Uchikawa et al, 2016). LGP2 has also been described as a necessary component of an effective IFN response during positive-sense picornavirus infection (Satoh et al, 2010).…”
Section: Rna Nucleic Acid Sensing In Viral Immunology and Autoimmunitymentioning
Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.
“…Like V proteins of other related paramyxoviruses, the V protein of MeV interacts with MDA5 and RIG-I-like receptor 2 (LGP2) at the same time, and the latter has been reported as both a coactivator of MDA5 and a negative regulator of both RIG-I and MDA5 [87,88,89]. By interacting with phosphoprotein phosphatase 1 α and γ (PP1α/γ), V protein can also prevent PP1-mediated activation of MDA5 [90].…”
Section: Interaction Between Mev and Cellular Factorsmentioning
The measles virus (MeV) is a contagious pathogenic RNA virus of the family Paramyxoviridae, genus Morbillivirus, that can cause serious symptoms and even fetal complications. Here, we summarize current molecular advances in MeV research, and emphasize the connection between host cells and MeV replication. Although measles has reemerged recently, the potential for its eradication is promising with significant progress in our understanding of the molecular mechanisms of its replication and host-pathogen interactions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
