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. 2021 Apr 12;11(1):7858.
doi: 10.1038/s41598-021-87251-6.

Coevolution underlies GPCR-G protein selectivity and functionality

Min Jae Seo  1 , Joongyu Heo  2 , Kyunghui Kim  2 , Ka Young Chung  3 , Wookyung Yu  4   5
Affiliations

Coevolution underlies GPCR-G protein selectivity and functionality

Min Jae Seo et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Structure and selectivity of GPCR and G protein. (a) Structure of GPCR-G protein complex. This structure is obtained from GPCRdb (modeling structure of 5HT2B-Gq complex). (b) Structure of G protein alpha subunit. It is consisted of Ras-like domain and α-helical domain (AHD). Please note that AHD is displaced in the GPCR-G protein complex structure in (a). (c) Approximate number of currently identified ligands, GPCRs and Gα families. (d) Diverse mechanism of GPCR-G protein activation. One GPCR can activate different G proteins, and one G protein can be activated by diverse GPCRs.
Figure 2
Figure 2
Overview of statistical coupling analysis (SCA). (a) Multiple sequence alignment is provided by GPCRdb (GPCRdb.org). (b) Calculation of Kullback–Leibler divergence for site-specific conservation and covariation between pairwise position. (c) Pairwise coevolution matrix is generated from (b). Then, through the noise cleaning and clustering process, sectors are defined.
Figure 3
Figure 3
GPCRs have coevolved sectors and a common conserved sector. (a) Sector matrix of 5-HT receptor. (b) Structure representations of sectors of 5-HT receptor. (c) Sector matrix of DA receptor. (d) Structure representations of sectors of DA receptor. DAR-Orange1 is colored in orange, and DAR-Orange2 is colored in yellow. (e) Kullback–Leibler divergence of sectors of 5-HT receptor. Mann–Whitney test is performed between sectors. (****p ≤ 1.00e−04) (f) Kullback–Leibler divergence of sectors of DA receptor. Mann–Whitney test is performed between sectors. (****p ≤ 1.00e−04) (g) Venn-diagram of matched residue between HTR-Blue sector and DAR-Blue sector. (h) Venn-diagram of matched residue between coevolved sectors of HTR and DAR. (i) Sector positions of HTR and DAR according to secondary structure. At DAR row of (i), Orange color represents DAR-Orange1 and yellow represents DAR-Orange2.
Figure 4
Figure 4
Functional networks in G protein from recognition to signal transduction. (a) Sector matrix of G protein. Three sectors (G-Red, G-Green, G-Blue) are existed and G-Blue sectors are subdivided into three subsectors (G-Blue1, G-Blue2, G-Blue3). (b) Structure representation of red sector. (c) Venn-diagram of matched residue between G-Red and selectivity barcode defined by previous work. (d) Structure representation of blue sectors. (e) Venn-diagram of matched residue between G-Blue and conserved residues defined by previous work. (f) Structure representation of green sector. (g) Venn-diagram of matched residues among G-Green, Selectivity barcode and conserved residue. Close form of G protein structure is the modeling structure by Alhadeff et al..
Figure 5
Figure 5
Red sectors are mediator between GPCR and G protein signaling. (a) Construction of new multiple sequence alignments for integrated analysis of GPCR-G protein. (b) Results of integrated SCA. Blurred matrices are original sector matrix of HTR and G protein. The cross section of each matrix is covariation between HTR sectors and G protein sectors. (c) Structure representation of HTR-Red and G-Red which have high coevolution signals. (d) Sequence logo and amino acids patterns of HTR-Red and G-Red interaction. In amino acid pattern figure, x, y axis represent the amino acid order of three letter code alphabetically from top to bottom, left to right. (one letter code order: ARNDCQEGHILKMFPSTWYV-, -represents gap). (e) Amino acid pattern analysis between HTR-Red and G-Red residues. Patterns of each color are explained in legend. Same shape in each column represents similar distribution of amino acids’ pair.
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