Coevolution underlies GPCR-G protein selectivity and functionality

Min Jae Seo,Kyunghui Kim,Wookyung Yu,Ka Young Chung,Joongyu Heo

doi:10.1038/s41598-021-87251-6

Min Jae Seo, Kyunghui Kim + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-87251-6

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Abstract

G protein-coupled receptors (GPCRs) regulate diverse physiological events, which makes them as the major targets for many approved drugs. G proteins are downstream molecules that receive signals from GPCRs and trigger cell responses. The GPCR-G protein selectivity mechanism on how they properly and timely interact is still unclear. Here, we analyzed model GPCRs (i.e. HTR, DAR) and Gα proteins with a coevolutionary tool, statistical coupling analysis. The results suggested that 5-hydroxytryptamine receptors and dopamine receptors have common conserved and coevolved residues. The Gα protein also have conserved and coevolved residues. These coevolved residues were implicated in the molecular functions of the analyzed proteins. We also found specific coevolving pairs related to the selectivity between GPCR and G protein were identified. We propose that these results would contribute to better understandings of not only the functional residues of GPCRs and Gα proteins but also GPCR-G protein selectivity mechanisms.

Highlights

G protein-coupled receptors (GPCRs) are one of the most important signal transduction systems to transmit extracellular signals into cells
The Gα subunit consists of a Ras-like domain and α-helical domain’, and the nucleotide-binding pocket is located between these two domains (Fig. 1b)
It is difficult to define the key components of selectivity determinants because approximately 30–40% of amino acids are defined as selectivity barcodes (Supplementary Fig. S5a)

Summary

Introduction

G protein-coupled receptors (GPCRs) are one of the most important signal transduction systems to transmit extracellular signals (e.g., light, odorants, and hormones) into cells. GPCRs regulate critical physiological functions including sense recognition, neural transmission, and hormonal r esponses[1] Since they play important roles in human physiology and p athology[2], GPCRs have been extensively studied over the past decades. Upon ligand-binding, the seven TM helices undergo conformational changes, which promote the interaction of the receptor with downstream signaling molecules in c ells[7]. To determine the GPCR-G protein coupling selectivity, Flock et al recently used an evolutionary a pproach[10]. They used the concepts of paralogue and orthologue conservation. GPCR-G protein selectivity, which are available at GPCRdb (https://GPCRdb.org) This concept explaining selectivity determinants is innovative and persuasive. Flock et al.[10] mainly focused on GPCR-G protein interface regions, they could not fully explain the effects on selective binding of other residues outside the GPCR-G protein interface

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