Evolutionary Pathways of Family A GPCRs

A lovely study showing divergence in Family/class A GPCRs:

Multidimensional Scaling Reveals the Main Evolutionary Pathways of Class A G-Protein-Coupled Receptors
J Pelé, H Abdi, M Moreau, D Thybert, M Chabbert. 2011. PLoS ONE 6(4): e19094.
CNRS UMR 6214 – INSERM 771, Angers, France; University of Texas at Dallas, USA.


Summary Of the Study

Key outcomes: They have revealed a non-uniform distribution of GPCRs in clusters, diverged into four groups. Their model supported a radiative evolution hypothesis of Family A GPCRs with peptide receptors as core of divergence.

Methods: Three dimensional mapping of human Family A GPCR sequences by metric multidimensional scaling analysis (MDS).

MDS is an ordination method for data clustering, in this case to determine sequence space; the sequences are represented in a low-dimensional Euclidean space.

A brief description on the procedure was as follows. Multiple sequence alignment (ClustalX; and GeneDoc manually refined) was performed and matrix of pairwise distances was computed, and the distance matrix D was analysed by MDS. MDS transformed the matrix D into a cross-product matrix S; eigendecomposition of the latter was applied to compute a factor score matrix F. The sequence space of the receptors were mapped onto the 3-D space. The mapped receptor sequences in the 3-D space was clustered by K-means, which was iterated a thousand times with random initial centroids. In sequence analysis, a sequence set was divided into a subset and its complement, and the correlation between a position of the multiple sequence alignment and the subsets was measured by the frequency correlation derived from chi-squared test. Relevant formulae and explanations in more detail can be found in the original publication above.

Regarding the evolution of human receptor subfamilies, corresponding supplementary sequences to the subfamilies were provided from four species: cnidarian (N. vectensis), nematode (C. elegans), chordate (C.intestinalis) and verbebrate (D. rerio) lineages.

Results: Non-olfactory receptors form a non-redundant set of 283 sequences (referred to as the active sequence set in the paper); most (93%) of these were classified into the 12 sub-families, each belonging to one of four groups, as indicated in the table below:

The table modified from Pelé et al. 2011. Numbers indicate the percentage of sequences. TM2 Pro between 2.58 and 2.60. The residue positions indicated with Ballesteros-Weinstein numbering scheme. WXFG motif is of ECL1 (Klco, Nikiforovich & Baranski 2006).


Distribution of subfamilies in animal kingdom:
From cnidarians to vertebrates: PEP, AMIN, LGR, OPN, and SO;
In bilaterians: AD;
In chordates: MEG, PTG, CHEM, MTN;
In vertebrates: PUR; and
In mammalian: MRG.
(Deville, Rey & Chabbert 2009; Fredriksson & Schioth 2005)

Also in the paper:
The original paper includes a figure which presents evolutionary drift of subfamilies, and a figure showing proline patterns of human GPCRs. The paper also discuss a few notably conserved residues.


References

Deville J, Rey J & Chabbert M. 2009. An indel in transmembrane helix 2 helps to trace the molecular evolution of class A G-protein-coupled receptors. J Mol Evol 68: 475–489.

Fredriksson R & Schioth HB. 2005. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67: 1414–1425.

Klco JM, Nikiforovich GV & Baranski TJ. 2006. Genetic Analysis of the First and Third Extracellular Loops of the C5a Receptor Reveals an Essential WXFG Motif in the First Loop. J Biol Chem. 281(17):12010–12019.