Abstract
BackgroundClass C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM). The VFTMs of the class C GPCRs is responsible for ligand recognition and binding, and share sequence similarity with bacterial periplasmic amino acid binding proteins (PBPs). An extensive phylogenetic investigation of the VFTMs was conducted by analyzing for functional divergence and testing for positive selection for five typical groups of the class C GPCRs. The altered selective constraints were determined to identify the sites that had undergone functional divergence via positive selection. In order to structurally demonstrate the pattern changes during the evolutionary process, three-dimensional (3D) structures of the GPCR VFTMs were modelled and reconstructed from ancestral VFTMs.ResultsOur results show that the altered selective constraints in the VFTMs of class C GPCRs are statistically significant. This implies that functional divergence played a key role in characterizing the functions of the VFTMs after gene duplication events. Meanwhile, positive selection is involved in the evolutionary process and drove the functional divergence of the VFTMs. Our results also reveal that three continuous duplication events occurred in order to shape the evolutionary topology of class C GPCRs. The five groups of the class C GPCRs have essentially different sites involved in functional divergence, which would have shaped the specific structures and functions of the VFTMs.ConclusionTaken together, our results show that functional divergence involved positive selection and is partially responsible for the evolutionary patterns of the class C GPCR VFTMs. The sites involved in functional divergence will provide more clues and candidates for further research on structural-function relationships of these modules as well as shedding light on the activation mechanism of the class C GPCRs.
Highlights
Class C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM)
By inspecting the amino-acid sites, we report that altered selective constraints derived from positive selection resulted in the functional divergence in the VFTM domains of class C GPCRs
Phylogeny inference of the VFTMs A phylogenetic analysis of the aligned protein sequences showed that the VFTMs of class C GPCRs fell into three major classes: the metabotropic glutamate receptors (mGluRs) class, a second sensing receptor class consisting of the Ca2+-sensing receptors (CaSR) and the T1R, and a third less related class consisting of two homologous subunits of the gammaaminobutyric acid type B receptors (GABABRs), GB1 and GB2
Summary
Class C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM). The class C GPCRs are mainly composed of metabotropic glutamate receptors (mGluRs), gammaaminobutyric acid type B receptors (GABABRs), Ca2+-sensing receptors (CaSR), taste receptors (T1R), pheromone receptors (V2R) and olfactory receptors[1,2] They play a key role in the physiology of various types of epilepsy as well as in nociception and drug addiction [5]. These receptors structurally possess an extracellular Venus flytrap module (VFTM) where agonists bind and a heptahelical transmembrane domain (HD) which is responsible for G protein activation [6,7,8,9,10,11]. The class C GPCRs can form homodimers whereas GABABR is a heterodimer and is composed of two homologous subunits, GABAB1 (GB1) and GABAB2 (GB2) [17,18,19,20,21]
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