There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini

doi:10.1016/S0006-291X(03)00026-3

Biochemical and Biophysical Research Communications

Volume 301, Issue 3, 14 February 2003, Pages 725-734

https://doi.org/10.1016/S0006-291X(03)00026-3 Get rights and content

Abstract

We report six novel members of the superfamily of human G-protein coupled receptors (GPCRs) found by searches in the human genome databases, termed GPR123, GPR124, GPR125, GPR126, GPR127, and GPR128. Phylogenetic analysis demonstrates that these are additional members of the family of GPCRs with long N-termini, previously termed EGF-7TM, LNB-7TM, B2 or LN-7TM, showing that there exist at least 30 such GPCRs in the human genome. Three of these receptors form their own phylogenetic cluster, while two other places in a cluster with the previously reported HE6 and GPR56 (TM7XN1) and one with EMR1-3. All the novel receptors have a GPS domain in their N-terminus, except GPR123, as well as long Ser/Thr rich regions forming mucin-like stalks. GPR124 and GPR125 have a leucine rich repeat (LRR), an immunoglobulin (Ig) domain, and a hormone-binding domain (HBD). The Ig domain shows similarities to motilin and titin, while the LRR domain shows similarities to LRIG1 and SLIT1-2. GPR127 has one EGF domain while GPR126 and GPR128 do not contain domains that are readily recognized in other proteins beyond the GPS domain. We found several human EST sequences for most of the receptors showing differential expression patterns, which may indicate that some of these receptors participate in central functions while others are more likely to have a role in the immune or reproductive systems.

Section snippets

Materials and methods

Identification of novel receptors. Sequences of known GPCRs from LN-7TM family (BAI1; NP_001693.1, BAI2; NP_001694.1, BAI3; NP_001695.1, CELSR1; NP_055061.1, CELSR2; NP_001399.1, CELSR3; NP_001398.1, CD97; NP_001775.1, EMR1; NP_001965.1, EMR2; NP_038475.1, EMR3; NP_115960.1, ETL; NP_071442.1, GPR97; AY140959, GPR110; AY140952, GPR111; AY140953, GPR112; AY140954, GPR113; AY140955, GPR114; AY140956, GPR115; AY140957, GPR116; AY140958, HE6 (GPR64); NP_005747.1, LEC1; NP_036434.1, LEC2; NP_055736.1

Results

We have recently published eight new LN-7TM receptors that were found through creation of Hidden Markov Models (HMM) based on previously known clan B and LN-TM7 receptors and a subsequent search of the human NCBI genome (http://www.ncbi.nlm.nih.gov). The Celera genome (http://www.celera.com) is however not searchable using HMMs. We therefore used the new sequences and the other LN-7TM sequences as baits for BLAST searches in the Celera genome. The result of the searches was six novel human

Discussion

The six novel receptors show clear overall structural and phylogenetic relationship to the LN-7TM receptors. Three of the new receptors (GPR123, GPR124, and GPR125) form a new separate cluster among the other LN-7TM receptors as shown in Fig. 1. Two of the receptors (GPR126 and GPR128) show phylogenetic relationship to HE6 and GPR56, which have been known for a few years, and three receptors that we recently described after searching the NCBI database with HMM models [10]. The sixth receptor

Acknowledgements

The studies were supported by the Swedish Research Council (VR, medicine), the Swedish Society for Medical Research (SSMF), Åke Wibergs Stiftelse, Petrus och Augusta Hedlunds Stiftelse, Svenska Läkaresällskapet, and Melacure Therapeutics AB, Uppsala, Sweden.

References (30)

D.R. Flower
Modelling G-protein-coupled receptors for drug design
Biochim. Biophys. Acta
(1999)
M.L. Parmentier et al.
Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution
Neuropharmacology
(2000)
M. Stacey et al.
LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors
Trends Biochem. Sci.
(2000)
C. Burge et al.
Prediction of complete gene structures in human genomic DNA
J. Mol. Biol.
(1997)
M. Stacey et al.
J. Biol. Chem.
(2002)
A.J. Zendman et al.
TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic
FEBS Lett.
(1999)
Y. Suzuki et al.
cDNA cloning of a novel membrane glycoprotein that is expressed specifically in glial cells in the mouse brain. LIG-1, a protein with leucine-rich repeats and immunoglobulin-like domains
J. Biol. Chem.
(1996)
Y. Suzuki et al.
Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia
FEBS Lett.
(2002)
K. Brose et al.
Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance
Cell
(1999)
A. Bagri et al.
Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain
Neuron
(2002)

J. Trinick

Titin and nebulin: protein rulers in muscle?

Trends Biochem. Sci.

(1994)

J. Abe et al.

Ig-hepta, a novel member of the G protein-coupled hepta-helical receptor (GPCR) family that has immunoglobulin-like repeats in a long N-terminal extracellular domain and defines a new subfamily of GPCRs

J. Biol. Chem.

(1999)

T. Nechiporuk et al.

ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily

J. Biol. Chem.

(2001)

J. Bockaert et al.

Molecular tinkering of G protein-coupled receptors: an evolutionary success

EMBO J.

(1999)

E.S. Lander

The International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome

Nature

(2001)

Cited by (103)

Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases
2024, Genes and Diseases
Adhesion G protein-coupled receptors (aGPCRs) are the second largest diverse group within the GPCR superfamily, which play critical roles in many physiological and pathological processes through cell–cell and cell–extracellular matrix interactions. The adhesion GPCR Adgrg6, also known as GPR126, is one of the better-characterized aGPCRs. GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals. Current studies have extended our understanding of GPR126-mediated roles during development and in human diseases. In this review, we highlighted these recent advances in GPR126 in expression profile, molecular structure, ligand–receptor interactions, and associated physiological and pathological functions in development and diseases.
7TM domain structures of adhesion GPCRs: what's new and what's missing?
2023, Trends in Biochemical Sciences
Adhesion-type G protein-coupled receptors (aGPCRs) have long resisted approaches to resolve the structural details of their heptahelical transmembrane (7TM) domains. Single-particle cryogenic electron microscopy (cryo-EM) has recently produced aGPCR 7TM domain structures for ADGRD1, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRF1, and ADGRL3. We review the unique properties, including the position and conformation of their activating tethered agonist (TA) and signaling motifs within the 7TM bundle, that the novel structures have helped to identify. We also discuss questions that the kaleidoscope of novel aGPCR 7TM domain structures have left unanswered. These concern the relative positions, orientations, and interactions of the 7TM and GPCR autoproteolysis-inducing (GAIN) domains with one another. Clarifying their interplay remains an important goal of future structural studies on aGPCRs.
The clinical relevance of the adhesion G protein-coupled receptor F5 for human diseases and cancers
2023, Biochimica et Biophysica Acta - Molecular Basis of Disease
Among the numerous adhesion G protein-coupled receptors (GPCRs), adhesion G protein-coupled estrogen receptor F5 (ADGRF5) contains unique domains in the long N-terminal tail which can determine cell-cell and cell-matrix interaction as well as cell adhesion. Nevertheless, the biology of ADGRF5 is complex and still poorly explored. Accumulating evidence suggests that the ADGRF5 activity is fundamental in health and disease. For instance, ADGRF5 is essential in the proper function of lungs and kidney as well as the endocrine system, and its signification in vascularization and tumorigenesis has been demonstrated. The most recent studies have provided findings about the diagnostic potential of ADGRF5 in osteoporosis and cancers, and ongoing studies suggest other diseases as well. Here, we elaborate on the current state of knowledge about the ADGRF5 in the physiology and pathophysiology of human diseases and highlight its high potential as a novel target in various therapeutic areas.
Adhesion G protein-coupled receptors—Structure and functions
2023, Progress in Molecular Biology and Translational Science
Citation Excerpt :
It took another 15 years to understand that this molecule also contains a 7-transmembrane (7TM) region, typical of GPCRs9 and to remark the high similarity to another leucocyte surface molecule, CD97/ADGRE5, that has been cloned and identified as member of the secretin-like receptor family just prior to this observation.10 The 1990’s and early 2000’s saw the identification of several more representatives11–18 of what would be classified as the adhesion family of GPCRs within the 2003 established GRAFS system.19 In contrast, the latrophilin-type aGPCRs were first recognized for their ability to bind alpha latrotoxin, the main component of the black widow spider venom just about the same time as work on F4/80 was initially presented.20
Adhesion G protein-coupled receptors (aGPCRs) are an ancient class of receptors that represent some of the largest transmembrane-integrated proteins in humans. First recognized as surface markers on immune cells, it took more than a decade to appreciate their 7-transmembrane structure, which is reminiscent of GPCRs. Roughly 30 years went by before the first functional proof of an interaction with a G protein was published. Besides classic features of GPCRs (extracellular N terminus, 7-transmembrane region, intracellular C terminus), aGPCRs display a distinct N-terminal structure, which harbors the highly conserved GPCR autoproteolysis-inducing (GAIN) domain with the GPCR proteolysis site (GPS) in addition to several functional domains. Several human diseases have been associated with variants of aGPCRs and subsequent animal models have been established to investigate these phenotypes. Much progress has been made in recent years to decipher the structure and functions of these receptors. This chapter gives an overview of our current understanding with respect to the molecular structural patterns governing aGPCR activation and the contribution of these giant molecules to the development of pathologies.
Adhesion GPCRs as a paradigm for understanding polycystin-1 G protein regulation
2020, Cellular Signalling
Citation Excerpt :
Two major classification systems exist for the GPCR superfamily. Within the vertebrate GRAFS classification system [Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin [68]], ADGRs comprise the second largest family with 33 and 31 members identified in the human and mouse genomes, respectively [69,70]. In the A-F classification system, which includes both vertebrates and invertebrates, ADGRs are considered a subgroup within the B clade (synonymous with the Secretin receptor family) sometimes referred to as B2.
Polycystin-1, whose mutation is the most frequent cause of autosomal dominant polycystic kidney disease, is an extremely large and multi-faceted membrane protein whose primary or proximal cyst-preventing function remains undetermined. Accumulating evidence supports the idea that modulation of cellular signaling by heterotrimeric G proteins is a critical function of polycystin-1. The presence of a cis-autocatalyzed, G protein-coupled receptor (GPCR) proteolytic cleavage site, or GPS, in its extracellular N-terminal domain immediately preceding the first transmembrane domain is one of the notable conserved features of the polycystin-1-like protein family, and also of the family of cell adhesion GPCRs. Adhesion GPCRs are one of five families within the GPCR superfamily and are distinguished by a large N-terminal extracellular region consisting of multiple adhesion modules with a GPS-containing GAIN domain and bimodal functions in cell adhesion and signal transduction. Recent advances from studies of adhesion GPCRs provide a new paradigm for unraveling the mechanisms by which polycystin-1-associated G protein signaling contributes to the pathogenesis of polycystic kidney disease. This review highlights the structural and functional features shared by polycystin-1 and the adhesion GPCRs and discusses the implications of such similarities for our further understanding of the functions of this complicated protein.
Expression of the adhesion G protein-coupled receptor A2 (adgra2) during Xenopus laevis development
2018, Gene Expression Patterns
Citation Excerpt :
The Xenopus laevis Adgra2 is 1306 amino acid (aa) long and features three main parts, a long extracellular, a seven transmembrane and a short intracellular part. The extracellular part furthermore contains a signal peptide, a domain containing five leucine-rich repeats, an immunoglobulin domain, a hormone receptor domain and a Gpcr proteolysis site (Fredriksson et al., 2003). The intracellular region ends with a highly conserved PDZ binding site.
The adhesion G protein-coupled receptor A2 (Adgra2) is a seven transmembrane receptor that has been described to be a regulator for angiogenesis in mice. Furthermore, the zebrafish ouchless mutant is unable to develop dorsal root ganglia through a disrupted trafficking of Adgra2. Besides RNA sequencing data, nothing is reported about Adgra2 in the south African crawled frog Xenopus laevis.
In this study, we investigated for the first time the spatio-temporal expression of adgra2 during early Xenopus embryogenesis in detail. In silico approaches showed that the genomic adgra2 region as well as the Adgra2 protein sequence is highly conserved among different species including Xenopus. RT-PCR experiments confirmed that embryonic adgra2 expression is primarily detected at the beginning of neurulation and is then present throughout the whole Xenopus embryogenesis until stage 42. Whole mount in situ hybridization approaches visualized adgra2 expression in many tissues during Xenopus embryogenesis such as the cardiovascular system including the heart, the migrating neural crest cells and the developing eye including the periocular mesenchyme. Our results indicate a role of Adgra2 for embryogenesis and are a good starting point for further functional studies during early vertebrate development.

View all citing articles on Scopus

View full text

There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini

Abstract

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Biochim. Biophys. Acta

Neuropharmacology

Trends Biochem. Sci.

J. Mol. Biol.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

Cell

Neuron

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

Molecular tinkering of G protein-coupled receptors: an evolutionary success

EMBO J.

The International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome

Nature