Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) play key role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors, promoting high affinity binding of arrestins, which precludes G protein coupling. Direct binding to active GPCRs activates GRKs, so that they selectively phosphorylate only the activated form of the receptor regardless of the accessibility of the substrate peptides within it and their Ser/Thr-containing sequence. Mammalian GRKs were classified into three main lineages, but earlier GRK evolution has not been studied. Here we show that GRKs emerged at the early stages of eukaryotic evolution via an insertion of a kinase similar to ribosomal protein S6 kinase into a loop in RGS domain. GRKs in Metazoa fall into two clades, one including GRK2 and GRK3, and the other consisting of all remaining GRKs, split into GRK1-GRK7 lineage and GRK4-GRK5-GRK6 lineage in vertebrates. One representative of each of the two ancient clades is found as early as placozoan Trichoplax adhaerens. Several protists, two oomycetes and unicellular brown algae have one GRK-like protein, suggesting that the insertion of a kinase domain into the RGS domain preceded the origin of Metazoa. The two GRK families acquired distinct structural units in the N- and C-termini responsible for membrane recruitment and receptor association. Thus, GRKs apparently emerged before animals and rapidly expanded in true Metazoa, most likely due to the need for rapid signalling adjustments in fast-moving animals.
Highlights
The discovery of activation-dependent rhodopsin phosphorylation almost 40 years ago [1,2] was soon followed by the description of ‘‘opsin kinase’’ that selectively phosphorylates light-activated rhodopsin [3]
Rhodopsin phosphorylation was shown to be necessary for its rapid deactivation, which led to the idea that similar mechanism may regulate the signalling by hormone receptors [4]
We detected the RH+kinase domain (KD) fusions in non-metazoan species, including the opisthokont Monosiga brevicolis, thought to be the unicellular eukaryote closest to Metazoa [36]; another opisthokont Capsaspora owczarzaki (ATCC 30864), a unicellular amoeboid parasite of tropical snails, that has recently emerged as another candidate sister clade of Metazoa [37]; late blight oomycete Phytophotra infestans; white rust oomycete Albugo laibachii Nc14; and brown alga Ectocarpus siliculosus
Summary
The discovery of activation-dependent rhodopsin phosphorylation almost 40 years ago [1,2] was soon followed by the description of ‘‘opsin kinase’’ (modern name GRK1) that selectively phosphorylates light-activated rhodopsin [3]. Rhodopsin phosphorylation was shown to be necessary for its rapid deactivation, which led to the idea that similar mechanism may regulate the signalling by hormone receptors [4] This hypothesis was proved for b2-adrenergic receptors [5,6] and many other GPCRs (reviewed in [7]). The sequence of the first member of GRK family, bARK, suggested that it likely belongs to a distinct branch of eukaryotic Ser-Thr protein kinases [15]. It is currently classified as GRK superfamily within the AGC kinase group [16]. This superfamily was expanded by cloning of bARK2 (GRK3) [17], GRK4 [18], GRK5 [19], and GRK6 [20], followed by cone-specific GRK7 [21]
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