Tracing the evolution of the heterotrimeric G protein α subunit in Metazoa

Abstract

BackgroundHeterotrimeric G proteins are fundamental signaling proteins composed of three subunits, Gα and a Gβγ dimer. The role of Gα as a molecular switch is critical for transmitting and amplifying intracellular signaling cascades initiated by an activated G protein Coupled Receptor (GPCR). Despite their biochemical and therapeutic importance, the study of G protein evolution has been limited to the scope of a few model organisms. Furthermore, of the five primary Gα subfamilies, the underlying gene structure of only two families has been thoroughly investigated outside of Mammalia evolution. Therefore our understanding of Gα emergence and evolution across phylogeny remains incomplete.ResultsWe have computationally identified the presence and absence of every Gα gene (GNA-) across all major branches of Deuterostomia and evaluated the conservation of the underlying exon-intron structures across these phylogenetic groups. We provide evidence of mutually exclusive exon inclusion through alternative splicing in specific lineages. Variations of splice site conservation and isoforms were found for several paralogs which coincide with conserved, putative motifs of DNA-/RNA-binding proteins. In addition to our curated gene annotations, within Primates, we identified 15 retrotranspositions, many of which have undergone pseudogenization. Most importantly, we find numerous deviations from previous findings regarding the presence and absence of individual GNA- genes, nuanced differences in phyla-specific gene copy numbers, novel paralog duplications and subsequent intron gain and loss events.ConclusionsOur curated annotations allow us to draw more accurate inferences regarding the emergence of all Gα family members across Metazoa and to present a new, updated theory of Gα evolution. Leveraging this, our results are critical for gaining new insights into the co-evolution of the Gα subunit and its many protein binding partners, especially therapeutically relevant G protein – GPCR signaling pathways which radiated in Vertebrata evolution.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1147-8) contains supplementary material, which is available to authorized users.

Rational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity

“…Previous X-ray crystallographic analysis revealed that G proteins from different organisms and subclasses share nearly identical structural features (9–16). They are composed of two domains, a GTPase “Ras-like” domain that is conserved in all members of the GTPase superfamily and is homologous to the monomeric GTPase Ras and an all-α-helical domain that is unique to heterotrimeric G proteins (17, 18).…”

Structural and Dynamical Basis of G Protein Inhibition by YM-254890 and FR900359: An Inhibitor in Action

“…G protein-coupled receptors (GPCRs) are responsible for the transduction of an extracellular stimuli into the cell. Inside the cell the stimulus is recognized by the heterotrimeric αβγ G proteins as downstream effectors to regulate a wide variety of physiological processes. , There are four major families of G proteins (G s , G i/o , G q/11 , G 12/13 ) which share their molecular architecture and basic signaling mechanism. − The α subunit of the heterotrimeric G protein consists of two domains: the GTP-binding (Ras) domain and the α-helical domain , which are connected by two hinge regions, called “linker I” and “switch I” tightly enclosing the guanine nucleotide. , In order to release and exchange the nucleotide, domain separation must occur either spontaneously or in response to a structural change, which was induced by the activated GPCR acting as a nucleotide exchange factor. − Additionally, the α, β, and γ subunits of the G protein dissociate and trigger the cellular responses through their downstream signaling cascades . Like GPCRs, which represent a major drug target class comprising the largest family of membrane protein receptors, the downstream G proteins represent promising drug targets .…”

Phototransduction in a marine sponge provides insights into the origin of animal vision

“…GC, PDE, and PLC are key signal transducers of ciliary and rhabdomeric opsin pathways, initiated through the binding of Goα, Gtα, and Gqα ( Lamb, 2013 ; Leung and Montell, 2017 ; Oakley and Pankey, 2008 ; Plachetzki and Oakley, 2007 ). Although Amphimedon possess a Gtα gene and two Gqα genes ( Krishnan and Schiöth, 2015 ; Lokits et al., 2018 ), they are not differentially expressed in the pigment ring over other cell types, providing no support for the use of one pathway over another. However, the larval behavioral assays suggest that the immediate downstream targets of the PLC pathway are conserved.…”