ArticleThe EMBO journal2012
A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.
Article in The EMBO journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 280 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
280 citing papers in PubMed, 460 citations in OpenAlex.
- Novel Roles of GPCRs in the Renal Collecting Duct.Physiology (Bethesda, Md.) · 2026Review
- Non-canonical cleavage of GPR125/ADGRA3 releases extracellular receptor fragments detectable in cerebrospinal fluid.iScience · 2026Article
- The isolated Stachel peptide of the adhesion G protein-coupled receptor ADGRG6 is predominantly disordered with local helical propensity.Biophysical journal · 2026Article
- Microbial GAIN domains undergo autoproteolysis and enable release of diverse cell-surface-associated proteins.Current biology : CB · 2026Article
- Review
- CD97/Cells · 2026Review
- Ligand-tuned extracellular domain dynamics are correlated with signaling states in an adhesion GPCR.Science advances · 2026Article
- Tethered agonist- and GAIN domain-independent signaling of an adhesion GPCR.Science advances · 2026Article
- Polycystin-1 and Cardiac Remodeling: From Mechanotransduction to Clinical Consequences.Circulation research · 2026Review
- The therapeutic potential of orphan adhesion G-protein-coupled receptors.Nature reviews. Drug discovery · 2026Review
- Adhesion G protein-coupled receptors.Pharmacological reviews · 2026Review
- Self-cleavage-dependent and -independent functions ofProceedings of the National Academy of Sciences of the United States of America · 2026Article
- EndothelialThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- The atypical adhesion GPCR ADGRA1 controls hippocampal inhibitory circuit function.Cell reports · 2026Article
- Structural basis of GAIN domain autoproteolysis and cleavage-resistance in the adhesion G-protein coupled receptors.Nature communications · 2026Article
- Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2.Cell chemical biology · 2026Article
- The expanding roles of adhesion GPCRs in neural circuit assembly.Molecules and cells · 2026Review
- Adgrg6/Gpr126 is required for compact wall integrity and establishing trabecular identity during cardiac trabeculation.Nature communications · 2026Article
- Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans.Nature communications · 2026Article
- Synaptic Cell Adhesion: A Structural Perspective.Advances in neurobiology · 2026Review
220 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents an integral part of a much larger ∼320-residue domain that we termed GPCR-Autoproteolysis INducing (GAIN) domain. Crystal structures of GAIN domains from two distantly related cell-adhesion GPCRs revealed a conserved novel fold in which the GPS motif forms five β-strands that are tightly integrated into the overall GAIN domain. The GAIN domain is evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. Functionally, the GAIN domain is both necessary and sufficient for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis. Thus, the GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.