Resurrecting ancestral structural dynamics of an antiviral immune receptor: adaptive binding pocket reorganization repeatedly shifts RNA preferenceReportar como inadecuado

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BMC Evolutionary Biology

, 16:241

Phylogenetics and phylogeography


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.

KeywordsRIG-I RIG-like receptors Ancestral reconstruction Antiviral immunity Evolution of immunity Molecular evolution Innate immunity Abbreviations5′pppFive-prime triphosphate

ASRAncestral sequence resurrection

dsRNADouble-stranded RNA

RDRNA recognition domain

RLRRIG-like receptor

Electronic supplementary materialThe online version of this article doi:10.1186-s12862-016-0818-6 contains supplementary material, which is available to authorized users.

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Autor: Charles Pugh - Oralia Kolaczkowski - Austin Manny - Bryan Korithoski - Bryan Kolaczkowski


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