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• W3047702677 abstract "Adhesion G protein–coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the N terminus of the G protein–coupling seven-transmembrane–spanning bundle. GAIN domain–mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently, there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological contexts. Adhesion G protein–coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the N terminus of the G protein–coupling seven-transmembrane–spanning bundle. GAIN domain–mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently, there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological contexts. G protein–coupled receptors (GPCRs) are the largest class of membrane receptors, comprising over 800 members in humans. The GPCR seven-transmembrane helical bundle (7TM) allows for regulation of distinct G protein signaling cascades in response to diverse extracellular stimuli. Due to a broad influence on health and disease, GPCRs are heavily investigated for pharmacological intervention and are the targets of many approved drugs (1Rask-Andersen M. Masuram S. Schiöth H.B. The druggable genome: evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication.Annu. Rev. Pharmacol. Toxicol. 2014; 54 (24016212): 9-2610.1146/annurev-pharmtox-011613-135943Crossref PubMed Scopus (161) Google Scholar). Consequently, study of each individual GPCR subclass will provide unique angles that are beneficial for the development of therapeutics. Canonically, GPCR signaling is initiated by agonist binding to its orthosteric site, which results in rearrangements of the transmembrane helices of the 7TM bundle to allow efficient heterotrimeric G protein coupling and activation. G protein α subunits exchange GDP for GTP, allowing for functional dissociation of Gβγ and activation of downstream effectors. GPCRs are divided into six classes as follows with in-class examples: Class A (rhodopsin-like), Class B (secretin), Class C (metabotropic glutamate), Class D (pheromone), Class E (cAMP), and Class F (Frizzled) (2Attwood T.K. Findlay J.B. Fingerprinting G-protein-coupled receptors.Protein Eng. 1994; 7 (8170923): 195-20310.1093/protein/7.2.195Crossref PubMed Google Scholar, 3Krishnan A. Almén M.S. Fredriksson R. Schiöth H.B. The origin of GPCRs: identification of mammalian like rhodopsin, adhesion, glutamate and frizzled GPCRs in fungi.PLoS ONE. 2012; 7 (22238661): e2981710.1371/journal.pone.0029817Crossref PubMed Scopus (105) Google Scholar, 4Fredriksson R. Lagerström M.C. Lundin L.G. Schiöth H.B. The G-protein-coupled receptors in the human genome form five main families: phylogenetic analysis, paralogon groups, and fingerprints.Mol. Pharmacol. 2003; 63 (12761335): 1256-127210.1124/mol.63.6.1256Crossref PubMed Scopus (1871) Google Scholar). Within this naming system, the adhesion GPCRs (AGPCRs) are family B members but have been more aptly termed subfamily B2, whereas the traditional Class B peptide hormone-binding GPCRs comprise subfamily B1. AGPCRs are distinguished not only by their large extracellular regions (ECRs) that contain a wide variety of adhesive subdomains, but also by the highly conserved GPCR autoproteolysis–inducing (GAIN) domain that constitutively self-cleaves the receptors into two fragments (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar). Whereas extensive work has been done to characterize AGPCRs, it is largely uncertain how they are activated in endogenous tissues. How protein ligand-ECR binding regulates the activation state of the 7TM bundle is arguably the most intensely studied problem in current AGPCR research. To date, mechanisms involving AGPCR fragment dissociation and modes of allosteric modulation in response to endogenous ligands have been proposed. Here, we sought to provide clarity to these activation mechanisms by detailing the structural topologies of AGPCRs, while examining the prospective actions of endogenous ligands. AGPCR activation models will be compared with established modes of activation of other GPCR classes. Select aspects of AGPCR physiological regulation will also be discussed as routes to receptor activation. The theories outlined in this review will provide a consistent framework for classification of endogenous AGPCR ligands as they are identified and develop thought of mechanistic considerations in advance of AGPCR structures that await solution. As knowledge of AGPCR function increases, the realization that this class of receptors are untapped therapeutic targets will increase, prompting efforts to target them. The 33 human adhesion GPCRs (ADGRs) are divided among nine subfamilies, ADGRA–G, -L, and -V, based on sequence similarity (6Bjarnadóttir T.K. Fredriksson R. Höglund P.J. Gloriam D.E. Lagerström M.C. Schiöth H.B. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors.Genomics. 2004; 84 (15203201): 23-3310.1016/j.ygeno.2003.12.004Crossref PubMed Scopus (0) Google Scholar, 7Hamann J. Aust G. Araç D. Engel F.B. Formstone C. Fredriksson R. Hall R.A. Harty B.L. Kirchhoff C. Knapp B. Krishnan A. Liebscher I. Lin H.-H. Martinelli D.C. Monk K.R. et al.International union of basic and clinical pharmacology. XCIV. Adhesion G protein–coupled receptors.Pharmacol. Rev. 2015; 67 (25713288): 338-36710.1124/pr.114.009647Crossref PubMed Scopus (0) Google Scholar). AGPCRs possess 7TM domains that are known to signal through heterotrimeric G proteins in many cases. The N-terminal ECRs range from hundreds to thousands of residues and often share common characteristics among receptors in the same subfamily. The ECRs contain a variety of adhesion related subdomains that are often repeated (Fig. 1A, multicolored nodules). For example, group E AGPCRs, which include the ADGRE (EMR (EGF-like module–containing mucin-like hormone receptor)) receptors, contain epidermal growth factor–like repeats that are found in many types of proteins that mediate cell-adhesive interactions (8McKnight A.J. Gordon S. EGF-TM7: a novel subfamily of seven-transmembrane-region leukocyte cell-surface molecules.Immunol. Today. 1996; 17 (8962632): 283-28710.1016/0167-5699(96)80546-9Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 9Lin H.-H. Stacey M. Hamann J. Gordon S. McKnight A.J. Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97.Genomics. 2000; 67 (10903844): 188-20010.1006/geno.2000.6238Crossref PubMed Scopus (0) Google Scholar). Twelve AGPCRs contain a ∼70-residue hormone-binding (HormR) domain located N-terminally to their GAIN domain. There has yet to be a report of a hormone that binds to an AGPCR, leading many to believe that the HormR domain has additional functions beyond hormone binding (Fig. 1E) (10Arac D. Strater N. Seiradake E. Understanding the structural basis of adhesion GPCR functions.Handb. Exp. Pharmacol. 2016; 234 (27832484): 67-8210.1007/978-3-319-41523-9_4Crossref PubMed Scopus (17) Google Scholar). Another interesting motif found in select adhesion GPCR ECRs is the sperm protein, enterokinase, and agrin (SEA) domain. This domain is found in ADGRF1 (GPR110), ADGRF5 (GPR116), and ADGRG6 (GPR126) (11Lum A.M. Wang B.B. Beck-Engeser G.B. Li L. Channa N. Wabl M. Orphan receptor GPR110, an oncogene overexpressed in lung and prostate cancer.BMC Cancer. 2010; 10 (20149256): 4010.1186/1471-2407-10-40Crossref PubMed Scopus (33) Google Scholar, 12Abe J. Fukuzawa T. Hirose S. Cleavage of Ig-Hepta at a “SEA” module and at a conserved G protein-coupled receptor proteolytic site.J. Biol. Chem. 2002; 277 (11973329): 23391-2339810.1074/jbc.M110877200Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 13Leon K. Cunningham R.L. Riback J.A. Feldman E. Li J. Sosnick T.R. Zhao M. Monk K.R. Araç D. Structural basis for adhesion G protein-coupled receptor Gpr126 function.Nat. Commun. 2020; 11 (31924782): 19410.1038/s41467-019-14040-1Crossref PubMed Scopus (8) Google Scholar). SEA domains mediate a second autoproteolytic cleavage event that is distinct from GAIN domain self-cleavage. Not much is known about the role of the SEA domain, but its function leaves open the possibility that these particular receptors have alternative modes of signaling regulation. At the C-terminal end of nearly every AGPCR ECR, ending 7–18 residues prior to the start of the first transmembrane span of the 7TM bundle, is the GAIN domain (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar) (Fig. 1A). A seminal finding in the AGPCR field was the X-ray crystallographic solution of GAIN domain structures (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar). GAIN domains are divided into two subdomains: an α-helix–rich GAINA and β-sandwich GAINB. Complete GAIN domains are ∼320 amino acids with variability typically observed within the GAINA subdomain. As indicated by its name, the GAIN domain is a fully self-sufficient protease that catalyzes constitutive autoproteolysis that splits the receptors into two fragments. Autoproteolytic cleavage is believed to be constitutive in most cases, but some studies have raised the possibility that cleavage might be regulated, although consideration of overexpression artifacts is also merited (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar, 14Hsiao C.C. Cheng K.F. Chen H.Y. Chou Y.H. Stacey M. Chang G.W. Lin H.H. Site-specific N-glycosylation regulates the GPS auto-proteolysis of CD97.FEBS Lett. 2009; 583 (19737555): 3285-329010.1016/j.febslet.2009.09.001Crossref PubMed Scopus (26) Google Scholar, 15Wei W. Hackmann K. Xu H. Germino G. Qian F. Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene.J. Biol. Chem. 2007; 282 (17525154): 21729-2173710.1074/jbc.M703218200Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). The receptor fragments remaining after self-cleavage are the extracellular N-terminal fragment (NTF) or ECR and the membrane-intercalated C-terminal fragment (CTF), which is also referred to as the GPCR or 7TM domain. A dense network of hydrogen bonds within the GAIN domain allows the NTF and CTF to remain noncovalently bound after self-proteolysis, which is considered to occur early during receptor biosynthesis in an intracellular compartment (16Nieberler M. Kittel R.J. Petrenko A.G. Lin H.H. Langenhan T. Control of adhesion GPCR function through proteolytic processing.Handb. Exp. Pharmacol. 2016; 234 (27832485): 83-10910.1007/978-3-319-41523-9_5Crossref PubMed Scopus (20) Google Scholar). The two-fragment holoreceptor is trafficked to the plasma membrane where it resides, poised for signaling. The AGPCR self-proteolysis reaction requires proper folding of the GAIN domain and occurs within GAINB when a conserved basic residue at the P2 position of the cleavage site abstracts a hydrogen from the side chain of the conserved, polar threonine (or serine) at the P1′ position (Fig. 1B) (17Lin H.H. Chang G.W. Davies J.Q. Stacey M. Harris J. Gordon S. Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif.J. Biol. Chem. 2004; 279 (15150276): 31823-3183210.1074/jbc.M402974200Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). AGPCR P2 site basic residues are most commonly histidines, such as His-836 in ADGRL1 (latrophilin (LPHN1)), but can be arginine, such as Arg-855 in ADGRB5 (BAI3) (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar). The proton abstraction initiates a nucleophilic attack of the carbonyl group of the P1 residue, which is most commonly leucine. The resulting ester intermediate is resolved by a final nucleophilic attack of a water molecule. The consensus self-cleavage site within the GAIN domains of most AGPCRs is HL/T. Prior to solution of the GAIN domain structure, the HL/T site and surrounding sequence was termed the GPCR proteolysis site (GPS), reflecting the idea that the minimal sequence was sufficient for proteolysis rather than the larger structure of the GAIN domain (18Krasnoperov V. Lu Y. Buryanovsky L. Neubert T.A. Ichtchenko K. Petrenko A.G. Post-translational proteolytic processing of the calcium-independent receptor of α-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor: role of the G protein-coupled receptor proteolysis site (GPS) motif.J. Biol. Chem. 2002; 277 (12270923): 46518-4652610.1074/jbc.M206415200Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Prömel S. Langenhan T. Araç D. Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins.Trends Pharmacol. Sci. 2013; 34 (23850273): 470-47810.1016/j.tips.2013.06.002Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 20Krasnoperov V. Bittner M.A. Holz R.W. Chepurny O. Petrenko A.G. Structural requirements for α-latrotoxin binding and α-latrotoxin-stimulated secretion: a study with calcium-independent receptor of α-latrotoxin (CIRL) deletion mutants.J. Biol. Chem. 1999; 274 (9920906): 3590-359610.1074/jbc.274.6.3590Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Given that this original definition has changed, GPS has now commonly come to mean the HL/T consensus site within the GAIN domain. The GPS is located 14–25 residues N-terminal to the start of the first transmembrane span (TM1). The start of the CTF, the P1′ threonine, is also immediately N-terminal to the first residue of the final (13th) β-strand of the β-sandwich structure that comprises the GAINB subdomain. Therefore, β-strand 13 is part of the CTF, but it is embedded within GAINB, and the GPS (i.e. HL/T) is essentially the loop that links β-strands 12 and 13 (Fig. 1C). β-Strand 13 sequences of adhesion GPCRs are highly conserved and very hydrophobic, which aligns with their location within the interior core of GAINB subdomain (Fig. 1 (C–E) and Table 1). β-Strand 13 is noncovalently bound by a dense network of ∼20 hydrogen bonds that hold it firmly within the GAINB subdomain (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar).Table 1Adhesion GPCR GPS and tethered agonist/β-Strand 13 sequences* ADGRA1 (GPR123) does not have a GAIN domain and thus does not have a GPS. Open table in a new tab * ADGRA1 (GPR123) does not have a GAIN domain and thus does not have a GPS. Within recent years, the stalk that connects TM1 to the GAIN domain and includes β-strand 13 has been named the adhesion GPCR tethered-peptide agonist (also referred to as the tethered agonist). This conserved sequence within multiple AGPCRs was shown independently by two groups to play a pivotal role in mediating receptor activation (21Stoveken H.M. Hajduczok A.G. Xu L. Tall G.G. Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist.Proc. Natl. Acad. Sci. U. S. A. 2015; 112 (25918380): 6194-619910.1073/pnas.1421785112Crossref PubMed Scopus (102) Google Scholar, 22Liebscher I. Schön J. Petersen S.C. Fischer L. Auerbach N. Demberg L.M. Mogha A. Cöster M. Simon K.-U. Rothemund S. Monk K.R. Schöneberg T. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133.Cell Rep. 2014; 9 (25533341): 2018-202610.1016/j.celrep.2014.11.036Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). One feature that seems to be an obvious requirement for tethered-peptide agonism is that the NTF and CTF of the receptor must become dissociated to liberate the agonist peptide from the interior core of the GAIN domain. Many within the field are currently deciphering exactly how AGPCR tethered agonism intersects with the varied AGPCR activation mechanisms, which are discussed below. Interestingly, not all AGPCRs undergo autoproteolysis; some receptors, including ADGRC1 (cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1)), ADGRA2 (GPR124), ADGRF2 (GPR111), ADGRA3 (GPR125), and ADGRF4 (GPR115), may be activated by alternative modes that do not involve fragment dissociation and tethered-peptide agonism (23Formstone C.J. Moxon C. Murdoch J. Little P. Mason I. Basal enrichment within neuroepithelia suggests novel function(s) for Celsr1 protein.Mol. Cell Neurosci. 2010; 44 (20353824): 210-22210.1016/j.mcn.2010.03.008Crossref PubMed Scopus (0) Google Scholar, 24Vallon M. Essler M. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin αvβ3 to glycosaminoglycans.J. Biol. Chem. 2006; 281 (16982628): 34179-3418810.1074/jbc.M605291200Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 25Prömel S. Waller-Evans H. Dixon J. Zahn D. Colledge W.H. Doran J. Carlton M.B.L. Grosse J. Schöneberg T. Russ A.P. Langenhan T. Characterization and functional study of a cluster of four highly conserved orphan adhesion-GPCR in mouse.Dev. Dyn. 2012; 241 (22837050): 1591-160210.1002/dvdy.23841Crossref PubMed Scopus (35) Google Scholar). Impaired self-cleavage is typically attributed to alterations of the GPS; receptors lacking a basic residue at the P2 position (e.g. ADGRF2 or ADGRF4) or a polar residue at the P1′ position. (e.g. ADGRC1) demonstrate minimal or no autoproteolysis (Table 1) (23Formstone C.J. Moxon C. Murdoch J. Little P. Mason I. Basal enrichment within neuroepithelia suggests novel function(s) for Celsr1 protein.Mol. Cell Neurosci. 2010; 44 (20353824): 210-22210.1016/j.mcn.2010.03.008Crossref PubMed Scopus (0) Google Scholar, 24Vallon M. Essler M. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin αvβ3 to glycosaminoglycans.J. Biol. Chem. 2006; 281 (16982628): 34179-3418810.1074/jbc.M605291200Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 25Prömel S. Waller-Evans H. Dixon J. Zahn D. Colledge W.H. Doran J. Carlton M.B.L. Grosse J. Schöneberg T. Russ A.P. Langenhan T. Characterization and functional study of a cluster of four highly conserved orphan adhesion-GPCR in mouse.Dev. Dyn. 2012; 241 (22837050): 1591-160210.1002/dvdy.23841Crossref PubMed Scopus (35) Google Scholar). Differences in post-translational modifications have also been proposed to regulate GAIN-mediated cleavage, such as N-linked glycosylation events within the GAIN domain (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.EMBO J. 2012; 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref PubMed Scopus (204) Google Scholar, 14Hsiao C.C. Cheng K.F. Chen H.Y. Chou Y.H. Stacey M. Chang G.W. Lin H.H. Site-specific N-glycosylation regulates the GPS auto-proteolysis of CD97.FEBS Lett. 2009; 583 (19737555): 3285-329010.1016/j.febslet.2009.09.001Crossref PubMed Scopus (26) Google Scholar, 15Wei W. Hackmann K. Xu H. Germino G. Qian F. Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene.J. Biol. Chem. 2007; 282 (17525154): 21729-2173710.1074/jbc.M703218200Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). However, observations of inefficient cleavage in these instances may be manifestations of experimental receptor overexpression that impart improper receptor trafficking or processing. Noncleaved AGPCRs are still capable of signaling, leaving open the question of how these receptors become activated. GPCRs exhibit different basal activity levels that depend on the individual characteristics of each receptor. Basal activity is one state that GPCRs occupy within a dynamic energy landscape of active and inactive conformations (26Manglik A. Kobilka B. The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin.Curr. Opin. Cell Biol. 2014; 27 (24534489): 136-14310.1016/j.ceb.2014.01.008Crossref PubMed Scopus (154) Google Scholar, 27Hilger D. Masureel M. Kobilka B.K. Structure and dynamics of GPCR signaling complexes.Nat. Struct. Mol. Biol. 2018; 25 (29323277): 4-1210.1038/s41594-017-0011-7Crossref PubMed Scopus (207) Google Scholar, 28Xu J. Hu Y. Kaindl J. Risel P. Hubner H. Maeda S. Niu X. Li H. Gmeiner P. Jin C. Kobilka B.K. Conformational complexity and dynamics in a muscarinic receptor revealed by NMR spectroscopy.Mol. Cell. 2019; 75 (31103421): 53-65.e5710.1016/j.molcel.2019.04.028Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Fig. 2 depicts four proposed activity states of adhesion GPCRs with cartoon diagrams that the field has used with representation of G protein–binding site dynamism as a function of receptor activation. Accompanying the diagrams are activity profiles of relative signaling strength. An understanding of the ways that AGPCRs become activated is emerging. There has been a broad and imaginative variety of proposed AGPCR activation schemes (10Arac D. Strater N. Seiradake E. Understanding the structural basis of adhesion GPCR functions.Handb. Exp. Pharmacol. 2016; 234 (27832484): 67-8210.1007/978-3-319-41523-9_4Crossref PubMed Scopus (17) Google Scholar, 29Purcell R.H. Hall R.A. Adhesion G protein–coupled receptors as drug targets.Annu. Rev. Pharmacol. Toxicol. 2018; 58 (28968187): 429-44910.1146/annurev-pharmtox-010617-052933Crossref PubMed Scopus (0) Google Scholar, 30Langenhan T. Adhesion G protein-coupled receptors—candidate metabotropic mechanosensors and novel drug targets.Basic Clin. Pharmacol. Toxicol. 2020; 126 (30859707): 5-1610.1111/bcpt.13223Crossref PubMed Scopus (6) Google Scholar, 31Kishore A. Hall R.A. Versatile signaling activity of adhesion GPCRs.Handb. Exp. Pharmacol. 2016; 234 (27832487): 127-14610.1007/978-3-319-41523-9_7Crossref PubMed Scopus (21) Google Scholar, 32Paavola K.J. Hall R.A. Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation.Mol. Pharmacol. 2012; 82 (22821233): 777-78310.1124/mol.112.080309Crossref PubMed Scopus (72) Google Scholar, 33Folts C.J. Giera S. Li T. Piao X. Adhesion G protein-coupled receptors as drug targets for neurological diseases.Trends Pharmacol. Sci. 2019; 40 (30871735): 278-29310.1016/j.tips.2019.02.003Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 34Liebscher I. Schoneberg T. Tethered agonism: a common activation mechanism of adhesion GPCRs.Handb. Exp. Pharmacol. 2016; 234 (27832486): 111-12510.1007/978-3-319-41523-9_6Crossref PubMed Scopus (28) Google Scholar). The current evidence supports two fundamental modes of AGPCR modulation: orthosteric agonism (i.e. tethered-peptide agonism), in which NTF/CTF dissociation is required, and allosteric regulation, which has also been termed the tunable model and does not require receptor subunit dissociation (21Stoveken H.M. Hajduczok A.G. Xu L. Tall G.G. Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist.Proc. Natl. Acad. Sci. U. S. A. 2015; 112 (25918380): 6194-619910.1073/pnas.1421785112Crossref PubMed Scopus (102) Google Scholar, 30Langenhan T. Adhesion G protein-coupled receptors—candidate metabotropic mechanosensors and novel drug targets.Basic Clin. Pharmacol. Toxicol. 2020; 126 (30859707): 5-1610.1111/bcpt.13223Crossref PubMed Scopus (6) Google Scholar, 31Kishore A. Hall R.A. Versatile signaling activity of adhesion GPCRs.Handb. Exp. Pharmacol. 2016; 234 (27832487): 127-14610.1007/978-3-319-41523-9_7Crossref PubMed Scopus (21) Google Scholar, 33Folts C.J. Giera S. Li T. Piao X. Adhesion G protein-coupled receptors as drug targets for neurological diseases.Trends Pharmacol. Sci. 2019; 40 (30871735): 278-29310.1016/j.tips.2019.02.003Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 35Langenhan T. Aust G. Hamann J. Sticky signaling–adhesion class G protein-coupled receptors take the stage.Sci. Signal. 2013; 6 (23695165): re310.1126/scisignal.2003825Crossref PubMed Scopus (151) Google Scholar). Both fundamental activation modes are supported through several lines of evidence, and it is likely that individual AGPCRs can be activated in both manners. Orthosteric agonism is a receptor activation model that depends on the action of the AGPCR tethered agonist. The most important residues, or the core of the tethered agonist, are the seven residues located immediately C-terminal to the GPS. These residues mostly overlap with β-strand 13, the conformation the sequence adopts in the holoreceptor form. The core residues share the consensus sequence TXFAVLM, with the T, F, and M residues showing the highest conversation across all AGPCRs (Table 1). Prior to understanding that this sequence was a tethered-peptide agonist, a study by Hall and colleagues (36Paavola K.J. Stephenson J.R. Ritter S.L. Alter S.P. Hall R.A. The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity.J. Biol. Chem. 2011; 286 (21708946): 28914-2892110.1074/jbc.M111.247973Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) provided evidence that an isolated CTF was more active than its cognate holoreceptor. The signaling strengths of ADGRG1 (GPR56) and an engineered ADGRG1 construct in which the entirety of the NTF was deleted (ΔNTF, or CTF) were compared. The ΔNTF receptor exhibited substantially higher G protein–dependent signaling than the full-length receptor (36Paavola K.J. Stephenson J.R. Ritter S.L. Alter S.P. Hall R.A. The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity.J. Biol. Chem. 2011; 286 (21708946): 28914-2892110.1074/jbc.M111.247973Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Since then, ΔNTF variants of several AGPCRs were found to have increased signaling capacity (21Stoveken H." @default.
• W3047702677 created "2020-08-13" @default.
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• W3047702677 date "2020-10-01" @default.
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• W3047702677 title "Mechanisms of adhesion G protein–coupled receptor activation" @default.
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