Multidimensional Scaling Reveals the Main Evolutionary Pathways of Class A G-Protein-Coupled Receptors

Abstract

Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families.

Genetic variation and species identification among selected leeches (Hirudinea) revealed by RAPD markers

“…The algorithm proved to be a powerful method in resolving evolution of grasses from the genus Lolium (Polok 2007) and repositioning of rodents, chiroptera and primates in phylogenetic trees (Milner et al 2004). This is a useful approach for a large set of data and with a growing number of molecular data MDS is seen a modern means for resolving phylogenetic trees, which was emphasized by using MDS in monitoring evolution of the largest family of transmembrane receptors (GPCRs) in humans (Pélé et al 2011). To visualize evolutionary relationBrought to you by | MIT Libraries Authenticated Download Date | 5/9/18 2:55 PM ships among studied leeches a number of dimensions were reduced from nine to three using the Guttman-Lingoes test.…”

Evolution of Class A G-Protein-Coupled Receptors: Implications for Molecular Modeling

“…The clustering of the human non-olfactory class A GPCRs into sub-families corresponds to the analysis reported by Pelé et al [50]. The nomenclature is adapted from [2].…”

“…They include several vertebrates [2,33,[35][36][37][38][39][40][41][42][43][44], an urochordate [36,45], a cephalochordate [46], an echinoderm [47,48], insects [33,36,49], a nematode [33,36], a cnidarian [34,50], a placazoan [34] and a poriferan [51]. These studies indicate that class A GPCRs are present in any animal genome investigated to date [33,34].…”

“…For clarity purpose, positions are numbered with the Ballesteros' numbering scheme [56] that attributes the number X. 50 to the most conserved residue in each helix X and uses this number as a relative reference. Fig.…”

“…The MECA sub-family proposed by Schioth et al [2] is the acronym for the evolutionary related melanocortin, EDG (Endothelial Differentiation G-protein-coupled), cannabinoid and adenosine receptors. In the classification shown in Table 2, it is split into the adenosine receptor sub-family (AD) and the melanocortin, EDG and cannabinoid receptor sub-family (MEC), on the basis of the evolutionary mechanism yielding the MEC receptors from ancestral AD receptors [50].…”