The intramolecular agonist is obligate for activation of glycoprotein hormone receptors

Schulze, Annelie; Kleinau, Gunnar; Neumann, Susanne; Scheerer, Patrick; Schöneberg, Torsten; Brüser, Antje

doi:10.1096/fj.202000100r

Cited by 19 publications

(11 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of GPR133, where the uncleavable H543R mutant demonstrates 60% of the basal activity of the WT cleaved receptor, it is possible that the Stachel sequence is already prebound in the agonist-binding site of the CTF and cleavage allows full isomerization to the active state. Such a model would be consistent with isomerization properties of other GPCRs with tethered agonists ( 33 , 34 , 35 ).…”

Section: Discussionsupporting

confidence: 66%

Functional impact of intramolecular cleavage and dissociation of adhesion G protein–coupled receptor GPR133 (ADGRD1) on canonical signaling

Frenster

Stephan

Ravn-Boess

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Discussionsupporting

confidence: 66%

Functional impact of intramolecular cleavage and dissociation of adhesion G protein–coupled receptor GPR133 (ADGRD1) on canonical signaling

Frenster

Stephan

Ravn-Boess

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the case of GPR133, where the uncleavable H543R mutant demonstrates 60% of the basal activity of the wild-type cleaved receptor, it is possible that the Stachel sequence is already prebound in the agonist binding site of the CTF and cleavage allows full isomerization to the active state. Such a model would be consistent with isomerization properties of other GPCRs with tethered agonists (Bruser et al, 2016; Schoneberg et al, 2016; Schulze et al, 2020).…”

Section: Discussionsupporting

confidence: 64%

Dissociation of the intramolecularly cleaved N- and C-terminal fragments of the adhesion G protein-coupled receptor GPR133 (ADGRD1) increases canonical signaling

Frenster

Stephan

Ravn-Boess

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

SUMMARYGPR133 (ADGRD1), an adhesion G protein-coupled receptor (GPCR), is necessary for growth of glioblastoma (GBM), a brain malignancy. The extracellular N-terminus of GPR133 is thought to be autoproteolytically cleaved into an N-terminal and a C-terminal fragment (NTF and CTF). Nevertheless, the role of this cleavage in receptor activation remains unclear. Here, we show that the wild-type (WT) receptor is cleaved after protein synthesis and generates significantly more canonical signaling than an uncleavable point mutant (H543R) in patient-derived GBM cultures and HEK293T cells. However, the resulting NTF and CTF remain non-covalently bound until the receptor is trafficked to the plasma membrane, where we find NTF-CTF dissociation. Using a fusion of the hPAR1 receptor N-terminus and the CTF of GPR133, we demonstrate that thrombin-induced cleavage and shedding of the hPAR1 NTF increases receptor signaling. This study supports a model where dissociation of the NTF at the plasma membrane promotes GPR133 activation.Highlights-GPR133 is intramolecularly cleaved in patient-derived GBM cultures-Cleaved GPR133 signals at higher efficacy than the uncleavable GPR133 H543R mutant-The N- and C-terminal fragments (NTF and CTF) of GPR133 dissociate at the plasma membrane-Acute thrombin-induced cleavage of the human PAR1 NTF from the GPR133 CTF increases signalingeTOC BlurbFrenster et al. demonstrate intramolecular cleavage of the adhesion GPCR GPR133 in glioblastoma and HEK293T cells. The resulting N- and C-terminal fragments dissociate at the plasma membrane to increase canonical signaling. The findings suggest dissociation of GPR133’s N-terminus at the plasma membrane represents a major mechanism of receptor activation.

show abstract

“…3e). Previous mutagenesis to other hydrophobic residues (T, L) at this site has been shown to increase basal and agonist-mediated cAMP accumulation 40 . Thus, we investigated whether lipid occupancy in this transmembrane pocket is important in activation of the TSHR.…”

Section: Agonist M22 Autoantibody Mimics Tsh To Activate Tshrmentioning

confidence: 99%

Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Faust

Singh

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

Thyroid hormones are vital to growth and metabolism. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves' disease. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright conformation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody selects a similar upright conformation of the extracellular domain. Conformational changes in the extracellular domain are transduced to the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane domain. Rotation of the TSHR ECD relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to G protein-coupled receptors with large extracellular domains.

show abstract

The intramolecular agonist is obligate for activation of glycoprotein hormone receptors

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 19 publications

References 79 publications

Functional impact of intramolecular cleavage and dissociation of adhesion G protein–coupled receptor GPR133 (ADGRD1) on canonical signaling

Functional impact of intramolecular cleavage and dissociation of adhesion G protein–coupled receptor GPR133 (ADGRD1) on canonical signaling

Dissociation of the intramolecularly cleaved N- and C-terminal fragments of the adhesion G protein-coupled receptor GPR133 (ADGRD1) increases canonical signaling

Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Contact Info

Product

Resources

About