title: Getting from A to B-exploring the activation motifs of the class B adhesion G protein-coupled receptor subfamily G member 4/GPR112.
abstract: The adhesion G protein-coupled receptors [ADGRs/class B2 G protein-coupled receptors (GPCRs)] constitute an ancient family of GPCRs that have recently been demonstrated to play important roles in cellular and developmental processes. Here, we describe a first insight into the structure-function relationship of ADGRs using the family member ADGR subfamily G member 4 (ADGRG4)/GPR112 as a model receptor. In a bioinformatics approach, we compared conserved, functional elements of the well-characterized class A and class B1 secretin-like GPCRs with the ADGRs. We identified several potential equivalent motifs and subjected those to mutational analysis. The importance of the mutated residues was evaluated by examining their effect on the high constitutive activity of the N-terminally truncated ADGRG4/GPR112 in a 1-receptor-1-G protein Saccharomyces cerevisiae screening system and was further confirmed in a transfected mammalian human embryonic kidney 293 cell line. We evaluated the results in light of the crystal structures of the class A adenosine A2A receptor and the class B1 corticotropin-releasing factor receptor 1. ADGRG4 proved to have functionally important motifs resembling class A, class B, and combined elements, but also a unique highly conserved ADGR motif (H3.33). Given the high conservation of these motifs and residues across the adhesion GPCR family, it can be assumed that these are general elements of ADGR function.-Peeters, M. C., Mos, I., Lenselink, E. B., Lucchesi, M., IJzerman, A. P., Schwartz, T. W. Getting from A to B-exploring the activation motifs of the class B adhesion G protein-coupled receptor subfamily G member 4/GPR112.
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands; and Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology, Faculty of Health Sciences, University of Copenhagen, Denmark m.c.peeters@lacdr.leidenuniv.nl.
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Peeters
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands; and.
authors.forename: Iris
authors.initials: I
authors.lastname: Mos
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands; and.
authors.forename: Eelke B
authors.initials: EB
authors.lastname: Lenselink
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands; and.
authors.forename: Martina
authors.initials: M
authors.lastname: Lucchesi
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands; and.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000595:Amino Acid Sequence; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011487:Protein Conformation; D000072417:Protein Domains; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C000621816:ADGRG4 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: activation mechanism; bioinformatics; constitutive activity; receptor signaling; structure–function relationship