The Evolutionary History of Vertebrate Adhesion GPCRs and Its Implication on Their Classification

Aline Wittlake,Torsten Schöneberg,Simone Prömel

doi:10.3390/ijms222111803

Abstract

Adhesion G protein-coupled receptors (aGPCRs) form a structurally separate class of GPCRs with an unresolved evolutionary history and classification. Based on phylogenetic relations of human aGPCRs, nine families (A–G, L, V) were distinguished. Taking advantage of available genome data, we determined the aGPCR repertoires in all vertebrate classes. Although most aGPCR families show a high numerical stability in vertebrate genomes, the full repertoire of family E, F, and G members appeared only after the fish–tetrapod split. We did not find any evidence for new aGPCR families in vertebrates which are not present in the human genome. Based on ortholog sequence alignments, selection analysis clearly indicated two types of tetrapod aGPCRs: (i) aGPCR under strong purifying selection in tetrapod evolution (families A, B, D, L, V); and (ii) aGPCR with signatures of positive selection in some tetrapod linages (families C, E, G, F). The alignments of aGPCRs also allowed for a revised definition of reference positions within the seven-transmembrane-helix domain (relative position numbering scheme). Based on our phylogenetic cluster analysis, we suggest a revised nomenclature of aGPCRs including their transcript variants. Herein, the former families E and L are combined to one family (L) and GPR128/ADGRG7 forms a separate family (E). Furthermore, our analyses provide valuable information about the (patho)physiological relevance of individual aGPCR members.

Highlights

With more than 800 genes G protein-coupled receptors (GPCRs) form the most abundant superfamily in the human genome [1,2]
The current classification of adhesion GPCRs (aGPCRs) comprises nine families, all found in the human genome (Figure 1)
The question remains whether all mammals are equipped with the same repertoire of aGPCRs

Summary

Introduction

With more than 800 genes G protein-coupled receptors (GPCRs) form the most abundant superfamily in the human genome [1,2]. Based on phylogenetic sequence relations, GPCRs have been grouped into five classes: Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin receptors, the so-called GRAFS classification [3,4]. The NC-IUPHAR classification considers non-vertebrate receptors and sorts GPCRs into class A (rhodopsin-like), class B (adhesion- and secretin-like), class C (metabotropic glutamate receptor–like), class. The class of adhesion GPCRs (aGPCRs) are involved in transducing mechanical forces [6,7,8] and in cell–cell and cell–matrix interactions [9]. This still underinvestigated class contains 33 mammalian receptor homologs, most of them with unknown physiological properties [9]. Adhesion GPCRs are equipped with adhesive structural folds (e.g., leucin-rich domain, Ig domain, pentraxin domain) and a G protein-coupled receptor

Methods

Results

Conclusion