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.
Highlights
Proteins with a seven transmembrane helix scaffold are widespread in the animal kingdom and are usually assumed to be G-protein-coupled receptors (GPCRs) by similarity with their vertebrate counterparts
Understanding the mechanisms that led to the diversification of this family would help decipher the specificity of the sequence-structure-function relationships of each sub-family and would improve drug design targeted to GPCRs
From the multiple sequence alignment (MSA) of the active sequences, we computed a matrix of pairwise distances, based on sequence identity
Summary
Proteins with a seven transmembrane helix scaffold are widespread in the animal kingdom and are usually assumed to be G-protein-coupled receptors (GPCRs) by similarity with their vertebrate counterparts. Because they transduce signals from a wide variety of chemical or physical stimuli, these receptors are involved in the perception by the cell of its environment and the regulation of most physiological functions [1].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
