Classification, Nomenclature, and Structural Aspects of Adhesion GPCRs.
Representation of the nine distinct aGPCR subfamilies and their unique N-terminal domain architecture. The illustration also shows the extracellular structural feature shared by all aGPCRs (except ADGRA1), known as the GPCR autoproteolysis-inducing (GAIN) domain, that mediates autoproteolysis and subsequent attachment of the cleaved NTF and CTF fragments The adhesion family of G protein-coupled receptors (aGPCRs) is unique among all GPCR families with long N-termini and multiple domains that are implicated in cell-cell and cell-matrix interactions. Initially, aGPCRs in the human genome were phylogenetically classified into nine distinct subfamilies based on their 7TM sequence similarity. This phylogenetic grouping of genes into subfamilies was found to be in congruence in closely related mammals and other vertebrates as well. Over the years, aGPCR repertoires have been mapped in many species including model organisms, and, currently, there is a growing interest in exploring the pharmacological aspects of aGPCRs. Nonetheless, the aGPCR nomenclature has been highly diverse because experts in the field have used different names for different family members based on their characteristics (e.g., epidermal growth factor-seven-span transmembrane (EGF-TM7)), but without harmonization with regard to nomenclature efforts. In order to facilitate naming of orthologs and other genetic variants in different species in the future, the Adhesion-GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposed a unified nomenclature for aGPCRs. Here, we review the classification and the most recent/current nomenclature of aGPCRs and as well discuss the structural topology of the extracellular domain (ECD)/N-terminal fragment (NTF) that is comparable with this 7TM subfamily classification. Of note, we systematically describe the structural domains in the ECD of aGPCR subfamilies and highlight their role in aGPCR-protein interactions.
Department of Neuroscience, Functional Pharmacology, Uppsala University, Biomedical Center, 593, Uppsala, 75 124, Sweden.
Arunkumar
A
Krishnan
Department of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, 1081HV, The Netherlands.
Saskia
S
Nijmeijer
Department of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, 1081HV, The Netherlands.
Chris
C
de Graaf
Department of Neuroscience, Functional Pharmacology, Uppsala University, Biomedical Center, 593, Uppsala, 75 124, Sweden. helgi.schioth@neuro.uu.se.
Helgi B
HB
Schiöth
D000818:Animals; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D010802:Phylogeny; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D009626:Terminology as Topic
D043562:Receptors, G-Protein-Coupled
Adhesion GPCRs; Classification; Drug targets; GAIN domain; Homologs; Mammals; Model organisms; Nomenclature; Pharmacology; Vertebrates