The identification and development of biased modulators of proximal G protein-coupled receptor (GPCR) signaling to prevent pathological disease progression has been at the forefront of recent drug discovery efforts. Recently, Fu et al. identified cartilage oligomeric matrix protein (COMP) as an endogenous negative allosteric modulator of β-arrestin (βarr)-dependent angiotensin II (Ang II) Type 1A receptor (AT1 A R) signaling, which attenuates the development of abdominal aortic aneurysm (AAA), a chronic inflammatory vascular disease lacking pharmacological treatment options.
There is now wide recognition that GPCRs exist within a spectrum of structures and that their ligands act to stabilize certain conformations to engage distinct proximal transducers.1 Classically, orthosteric GPCR agonists induce conformations of their cognate receptors to elicit both G protein activation, to induce a rapid signaling response, and GPCR kinase (GRK)-dependent recruitment of the ubiquitous scaffolding proteins βarr1 and βarr2, which act to desensitize the receptor and/or maintain additional signaling responses.2 However, compared to a reference “gold standard” agonist, such as a natural endogenous agonist,3 some GPCR ligands more strongly promote G protein activation versus βarr recruitment, or vice versa. The relative ability of a ligand to elicit a stronger activation of one signaling response over another has been termed biased agonism. Additionally, endogenous allosteric modulators of GPCRs have been identified in recent years to be able to impart negative or positive signaling bias by changing the effect of the natural ligand on its GPCR structure.4 As studies have increasingly shown that biased modulation of GPCRs can relay differential outcomes in a cell-specific manner, harnessing this property to promote beneficial, and prevent pathologic, outcomes during disease progression has become a therapeutic goal of recent drug discovery efforts.
AT1AR in particular has been explored for many years in relation to the ability of designer orthosteric ligands to induce signal bias in comparison to Ang II. AT1AR is widely expressed throughout the cardiovascular system and regulates cardiac, vascular and renal effects, chronic activation of which can contribute to the development of numerous cardiovascular pathologies.5 Thus far, application of biased AT1AR ligand pharmacology to a pathologic condition has centered on the ability of Ang II-derived peptides to promote βarr-dependent cardiac contractility in the absence of maladaptive Gq protein-dependent remodeling during heart failure (reviewed in2). Mechanistically, recent studies using protein crystallography, advanced spectroscopy and molecular simulations of AT1AR with modified peptide ligands have begun to define how these orthosteric agonists induce biased signaling at a structural level, revealing combinations of transmembrane domain movements associated with differing degrees of a fully activated Gq protein-bound state and an occluded state allowing βarr coupling (reviewed in1). Since AT1AR biased ligand discovery efforts have mainly centered on synthetic orthosteric ligands, whether endogenous biased allosteric modulators of AT1AR exist and impart pathophysiologically-relevant outcomes on Ang II-mediated signaling has been unclear.
Publishing recently in Cell Research, Fu et al. have identified COMP as an endogenous negative allosteric modulator of βarr-dependent AT1AR signaling that dampens AAA incidence.6 This is an exciting study for many reasons, including that local expression and secretion of COMP within blood vessels themselves would allow it to mediate vascular homeostasis and dampen AAA development via regulation of various AT1AR-expressing cell types (Fig. 1). This would be consistent with previous reports demonstrating that although global AT1AR deletion protects against AAA in a mouse model of AAA, neither endothelial cell- nor vascular smooth muscle cell (VMSC)-specific AT1AR deletion was sufficient to do so,7 and that monocyte-expressing AT1AR contributes to the development of AAA.8 Translationally, the authors report that a decrease in plasma COMP level is negatively associated with human AAA, which was also observed more specifically in the suprarenal aortas of chronic Ang II-infused ApoE−/− mice, a common AAA model. Further, the authors demonstrate that COMP deficiency (COMP−/−) even on a wild-type background (C57BL/6) leads to increased incidence of AAA in response to Ang II infusion; however, crossing COMP−/− mice with AT1AR−/− mice, or overexpressing COMP either generally within the suprarenal aorta or specifically in VMSC, protects against AAA.6
To understand the mechanism by which COMP acts at AT1AR to oppose AAA development, Fu et al. performed an extensive series of molecular assays and found that COMP directly binds to the N-terminus of AT1AR, which neither decreases Ang II binding to its orthosteric site nor modulates Gq protein activation or downstream signaling.6 Rather, COMP acts to attenuate the ability of AT1AR to engage its high-affinity βarr-binding conformation in response to Ang II, thereby decreasing βarr recruitment and its associated functions including AT1AR internalization and desensitization. Thus, COMP acts as a negative allosteric modulator of βarr-dependent AT1AR signaling; however, the conformational changes of AT1AR induced by COMP to relay this effect remain unclear. Based on the structural changes that have been reported to occur within AT1AR in response to modified orthosteric ligands,1 COMP presumably promotes the distribution of Ang II-occupied AT1AR toward its fully active Gq protein-coupled state and away from its transducer-occluded state, thereby reducing βarr coupling. Regardless of the structural effect of COMP at the level of the receptor, its negative regulatory impact on AT1AR-mediated βarr signaling fits well with the previously reported observation that βarr2 deficiency attenuated AAA formation.9 In that study, βarr2 deletion was associated with reduced aortic inflammation and remodeling responses to Ang II infusion, effects consistent with the enhanced aortic inflammatory readouts in COMP−/− mice observed by Fu et al. that were reversed by crossing COMP−/− and βarr2−/− mice,6 and consistent with known βarr2-dependent effects on the regulation of inflammatory signaling.10
Finally, to advance their findings toward a therapeutic strategy, Fu et al. identified one of four different EGF repeat motifs within COMP, specifically EGF2, that directly interacts with the N-terminus of AT1AR and is required for COMP interaction with the receptor,6 orienting the C-terminus of COMP toward the first extracellular loop (ECL1) of AT1AR. Impressively, suprarenal aortic overexpression of a peptide encoding EGF2 was sufficient to decrease Ang II-induced AAA incidence in the ApoE−/− mouse model. This suggests that the orientation of C-terminal COMP with ECL1 of AT1AR is dispensable for the negative allosteric regulation of the receptor and that the interaction between EGF2 and the N-terminus of AT1AR alone may induce the required conformational changes to antagonize Ang II-mediated βarr recruitment. Thus, a pharmacologic strategy to allosterically modulate the N-terminus of AT1AR may offer a new approach to attenuate AAA incidence via biased antagonism of βarr-dependent aortic inflammation.
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Okyere, A.D., Tilley, D.G. Self-made allostery: endogenous COMP antagonizes pathologic AT1AR signaling. Cell Res (2021). https://doi.org/10.1038/s41422-021-00493-x