Stachel-mediated activation of adhesion G protein-coupled receptors: insights from cryo-EM studies

Liebscher, Ines; Schöneberg, Torsten; Thor, Doreen

doi:10.1038/s41392-022-01083-y

Cited by 22 publications

(17 citation statements)

References 5 publications

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“…As mentioned above, not all aGPCRs are auto-proteolytically cleaved; therefore, activation cannot be fully dependent on TA exposure through removal of the NTF (Kishore et al, 2016; Liebscher et al, 2022). In this regard, it is possible that FL aGPCRs exist in multiple conformational states that include receptor molecules in which the TA is unmasked from the GAIN domain.…”

Section: Discussionmentioning

confidence: 99%

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

Pederick

Perry-Hauser

Meng

et al. 2022

Preprint

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The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a receptor in distal CA1 neurons to direct their axons to proximal subiculum, and as a repulsive ligand in proximal subiculum to direct proximal CA1 axons to distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to Gα12/13 in heterologous cells, which is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2’s tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor. By contrast, neither tethered agonist activity nor autoproteolysis was necessary for Lphn2’s role as a repulsive ligand. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

Pederick

Perry-Hauser

Meng

et al. 2022

Preprint

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“…As other ADGRs, VLGR1 is composed of an extracellular N-terminal fragment (adhesion part), which is extremely long in VLGR1, fused by a GAIN domain, which includes the GPCR autoproteolytic cleavage site (GPS) to a C-terminal fragment defined by 7TM domain (receptor part) (Figure 1A). Evidence suggests that autocleavage at GPS exposes the short so-called "spike" sequence at the N-terminal end of CTF, which serves as a bound agonist to activate aGPCRs 3,4 . In VLGR1, we have recently identified 11 amino acids that act as the "Stachel" peptide 5 .…”

Section: Introductionmentioning

confidence: 99%

The adhesion G-protein coupled receptor VLGR1/ADGRV1 controls autophagy

Linnert

Güler

Krzysko

et al. 2023

Preprint

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VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest known adhesion G protein-coupled receptor. Mutations in VLGR1/ADGRV1 cause Usher syndrome (USH), the most common form of hereditary deaf-blindness, and have been additionally linked to epilepsy. Although VLGR1/ADGRV1 is almost ubiquitously expressed, little is known about the subcellular function and signalling of the VLGR1 protein and thus about mechanisms underlying the development of diseases. Using affinity proteomics, we have identified key components of autophagosomes as putative interacting proteins of VLGR1. In addition, whole transcriptome sequencing of the retinae of the Vlgr1/del7TM mouse model revealed altered expression profiles of gene-related autophagy. Monitoring autophagy by immunoblotting and immunocytochemistry of the LC3 and p62 as autophagy marker proteins revealed evoked autophagy in VLGR1-deficient hTERT-RPE1 cells and USH2C patient-derived fibroblasts. Our data demonstrate the molecular and functional interaction of VLGR1 with key components of the autophagy process and point to an essential role of VLGR1 in the regulation of autophagy at internal membranes. The close association of VLGR1 with autophagy helps to explain the pathomechanisms underlying human USH and epilepsy-related to VLGR1 defects.

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“…Autocleavage at the auto proteolysis site (GPS) localized within GAIN (GPCR auto-proteolysis-inducing) domain leads to a C-terminal fragment (CTF) and an N-terminal fragment (NTF) which can function independently 4,5 . There is growing evidence that after autocleavage the short so-called "Stachel" sequence in the very N-terminal end of CTF is exposed and can act as a tethered agonist activating aGPCRs 6,7 . We have recently found an 11 amino acid sequence as the "Stachel" peptide of VLGR1 8 .…”

Section: Introductionmentioning

confidence: 99%

The adhesion GPCR VLGR1/ADGRV1 regulates focal adhesion turnover by controlling their assembly

Güler

Linnert

Wolfrum

2023

Preprint

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VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest adhesion G protein-coupled receptor aGPCRs. Mutations in VLGR1/ADGRV1 are associated with human Usher syndrome (USH), the most common form of deaf-blindness, and also with epilepsy in humans and in mice. Although VLGR1 is almost ubiquitously expressed in CNS and ocular and inner ear sensory cells. Little is known about the pathogenesis of the diseases related to VLGR1. We previously identified VLGR1 as a vital component of focal adhesions (FA) serving as a metabotropic mechanoreceptor that controls cell spreading and migration. FAs are highly dynamic and turnover frequently in response to internal and external signals. Here, we aimed to elucidate how VLGR1 participates in FA turnover. Nocodazole washout assays and live-cell imaging of RFP-paxillin consistently demonstrated that FA disassembly was not altered, de novo assembly of FA was significantly delayed in Vlgr1-deficient astrocytes indicating that VLGR1 is enrolled in the assembly of FAs. In FRAP experiments recovery rates were significantly reduced in Vlgr1-deficient FAs, indicating reduced turnover kinetics in VLGR1-deficient FAs. We showed that VLGR1 regulates cell migration by controlling the FA turnover during their assembly. From this, we expect novel insights into pathomechanisms related to pathogenic dysfunctions of VLGR1.

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Stachel-mediated activation of adhesion G protein-coupled receptors: insights from cryo-EM studies

Cited by 22 publications

References 5 publications

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

The adhesion G-protein coupled receptor VLGR1/ADGRV1 controls autophagy

The adhesion GPCR VLGR1/ADGRV1 regulates focal adhesion turnover by controlling their assembly

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