Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain

Beliu, Gerti; Altrichter, Steffen; Guixà-González, Ramón; Hemberger, Mareike; Brauer, Ina; Dahse, Anne-Kristin; Scholz, Nicole; Wieduwild, Robert; Kuhlemann, Alexander; Batebi, Hossein; Seufert, Florian; Pérez‐Hernández, Guillermo; Hildebrand, Peter W.; Sauer, Markus; Langenhan, Tobias

doi:10.1016/j.molcel.2020.12.042

Cited by 62 publications

(66 citation statements)

References 74 publications

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“…Likewise, several GPR56-specific monobodies were found to activate the same GPR56-F385A mutant efficiently [ 47 ]. These results indicated that these specific agonists bind to the ECR of GPR56 and cause a unique conformational change that activates the receptor without the need of its proteolytic modification, hence supporting the GPS cleavage-independent activation mechanism of GPR56 [ 55 ].…”

Section: Overview Of the Adgrg1/gpr56 Receptormentioning

confidence: 78%

Role of ADGRG1/GPR56 in Tumor Progression

Chen

Stacey

et al. 2021

Cells

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Cellular communication plays a critical role in diverse aspects of tumorigenesis including tumor cell growth/death, adhesion/detachment, migration/invasion, angiogenesis, and metastasis. G protein-coupled receptors (GPCRs) which constitute the largest group of cell surface receptors are known to play fundamental roles in all these processes. When considering the importance of GPCRs in tumorigenesis, the adhesion GPCRs (aGPCRs) are unique due to their hybrid structural organization of a long extracellular cell-adhesive domain and a seven-transmembrane signaling domain. Indeed, aGPCRs have been increasingly shown to be associated with tumor development by participating in tumor cell interaction and signaling. ADGRG1/GPR56, a representative tumor-associated aGPCR, is recognized as a potential biomarker/prognostic factor of specific cancer types with both tumor-suppressive and tumor-promoting functions. We summarize herein the latest findings of the role of ADGRG1/GPR56 in tumor progression.

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Section: Overview Of the Adgrg1/gpr56 Receptormentioning

confidence: 78%

Role of ADGRG1/GPR56 in Tumor Progression

Chen

Stacey

et al. 2021

Cells

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“…In support of the ability for PC1 NTF-CTF subunits to dissociate, it has been shown that treatment of cells with an alkaline solution will lead to release of the NTF from the CTF in the membrane (55), and there is evidence that the PC1 CTF subunit exists by itself, i.e., dissociated from NTF, in vivo (47). Interestingly though, flexibility within the GAIN domain was recently shown to allow transient exposure of parts of the encrypted TA of a number of AdGPCRs (56), which may underlie the proposed allosteric activation mechanism whereby ligand-binding to the ectodomain enables signaling in absence of NTF removal and may account for the signaling ability of some GPS cleavage-deficient AdGPCRs (57-60). It will be important to determine whether the PC1 GAIN domain also exhibits such characteristics in future investigations.…”

Section: Discussionmentioning

confidence: 99%

Constitutive signaling by the C-terminal fragment of polycystin-1 is mediated by a tethered peptide agonist

Magenheimer

Munoz

Ravichandran

et al. 2021

Preprint

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Mutation of the PKD1 gene, encoding polycystin-1 (PC1), is the primary cause of autosomal dominant polycystic kidney disease. PC1 is an 11-transmembrane domain protein that binds and modulates the activity of multiple heterotrimeric G protein families and is thought to function as a non-canonical G protein-coupled receptor (GPCR). PC1 shares a conserved GPCR autoproteolysis inducing [GAIN] domain with the adhesion family of GPCRs, that promotes an auto-catalytic, cis-cleavage at the GPCR proteolysis site (GPS) located proximal to the first transmembrane domain. GPS cleavage divides these receptors into two associated ‘subunits’, the extracellular N-terminal (NTF) and transmembrane C-terminal (CTF) fragments. For the adhesion GPCRs, removal of the NTF leads to activation of G protein signaling as a result of the exposure and subsequent intramolecular binding of the extracellular N-terminal stalk of the CTF, i.e., the tethered cryptic ligand or tethered agonist model. Here, we test the hypothesis that PC1-mediated signaling is regulated by an adhesion GPCR-like, tethered agonist mechanism. Using cell-based reporter assays and mutagenesis of PC1 expression constructs, we show that the CTF form of PC1 requires the stalk for signaling activation and synthetic peptides derived from the PC1 stalk sequence can re-activate signaling by a ‘stalk-less’ CTF. In addition, we demonstrate that ADPKD-associated missense mutations within the PC1 stalk affect signaling and can inhibit GPS cleavage. These results provide a foundation for beginning to understand the molecular mechanism of G protein regulation by PC1 and suggest that a tethered agonist-mediated mechanism can contribute to PKD pathogenesis.SIGNIFICANCE STATEMENTMutations of the PKD1 gene, encoding polycystin-1, are the predominant cause of autosomal dominant polycystic kidney disease (ADPKD), a systemic disease that is the 4th leading cause of kidney failure. Polycystin-1 functions as an atypical GPCR capable of binding or activating heterotrimeric G proteins, which is essential for preventing renal cystogenesis. However, little is known regarding its regulation. Polycystin-1 shares structural features with the Adhesion family of GPCRs. In this work, we combined mutagenesis and cellular signaling assays which demonstrated that constitutive activation of signaling by polycystin-1 involves an Adhesion GPCR-like molecular mechanism. This study provides new knowledge regarding the structure-function relationships of polycystin-1 which will stimulate additional areas of investigation and reveal novel avenues of therapeutic intervention for ADPKD.

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“…While these conformational GPCR sensors exclusively detect the receptors' structural dynamics at the intracellular side, several FRET-based GPCR sensors have been devised to study the extracellular conformational rearrangements of mainly class C GPCRs labeled using SNAP-and CLIP-tag technology (29)(30)(31). In addition, genetic code expansion and labeling of unnatural amino acids (uaas) enabled the investigation of tethered agonist ("Stachel") exposure in class adhesion GPCRs (32).…”

Section: Introductionmentioning

confidence: 99%