The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints

TLDR

The superfamily of G‑protein‑coupled receptors (GPCRs) is highly diverse in structure and function and is among the most pursued targets for drug development. The study proposes a novel approach to analyze large, diverse GPCR sequence sets to aid research on GPCRs in other genomes and divergent protein families. The authors identified over 800 human GPCR sequences, performed phylogenetic analyses on 342 unique nonolfactory receptors, examined paralogon positions to infer duplication events, and used Hidden Markov Models to detect fingerprint motifs linking GRAFS families. The analysis revealed a robust GRAFS classification of five main families—glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin—with the rhodopsin family being the largest, and identified shared structural motifs that suggest a common ancestor, thereby providing the first comprehensive map of human GPCRs in a single genome.

Abstract

The superfamily of G-protein-coupled receptors (GPCRs) is very diverse in structure and function and its members are among the most pursued targets for drug development. We identified more than 800 human GPCR sequences and simultaneously analyzed 342 unique functional nonolfactory human GPCR sequences with phylogenetic analyses. Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system. The rhodopsin family is the largest and forms four main groups with 13 sub-branches. Positions of the GPCRs in chromosomal paralogons regions indicate the importance of tetraploidizations or local gene duplication events for their creation. We also searched for "fingerprint" motifs using Hidden Markov Models delineating the putative inter-relationship of the GRAFS families. We show several common structural features indicating that the human GPCRs in the GRAFS families share a common ancestor. This study represents the first overall map of the GPCRs in a single mammalian genome. Our novel approach of analyzing such large and diverse sequence sets may be useful for studies on GPCRs in other genomes and divergent protein families.