ADGRA1 (GPR123) is a brain-enriched seven-transmembrane receptor and the structural outlier of the adhesion G protein-coupled receptor family: unlike the other 32 human members it has no extracellular adhesion modules and no GAIN/GPS domain, its canonical isoform presenting only a 19-residue extracellular N-terminus ahead of the first transmembrane helix. Its bulk lies inside the cell, in a 255-residue cytoplasmic tail that terminates in a class I PDZ-binding motif (ETTV). Through that motif the receptor binds the PDZ domains of a wide set of membrane-associated scaffolds - the DLG/MAGUK proteins DLG1-4, MAGI1/2, SCRIB, MPDZ, PATJ, GRIP1/2, LNX1/2 and others - with micromolar affinities, placing it within postsynaptic scaffold networks. In the mammalian brain the receptor is enriched in thalamic nuclei, deep cortical layers, amygdala, hypothalamus and hippocampus, and localises to postsynaptic compartments and to a subset of synapses. In the hippocampus it is selectively enriched in parvalbumin-positive inhibitory interneurons, where it is required for their intrinsic excitability and for the strength of the inhibitory synapses they make onto dentate gyrus granule cells. No agonist is known, and the receptor activates heterotrimeric G proteins - most notably Galpha13, along with Galpha11 and Galpha15 - in an agonist-independent manner that does not require its short extracellular segment, suggesting it is regulated by localisation rather than by ligand binding. Loss of the receptor in mice also raises energy expenditure and thermogenesis and increases anxiety-like behaviour, and the human protein is required for maintenance of pluripotency in pluripotent stem cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Correct, but note the donor set is entirely paralogous: node PTN001738137 spans ADGRA1/2/3 and all five non-node WITH/FROM tokens are ADGRA2 or ADGRA3. Reason: Provenance and circularity are separate claims and only the second carries a verdict. Provenance: 5 of 5 protein donors on this row are ADGRA2/ADGRA3 (mouse Adgra2 Q91ZV8, mouse Adgra3 Q7TT36, human ADGRA2 Q96PE1, zebrafish adgra2, zebrafish adgra3); not one is an ADGRA1 ortholog. On its own that supports nothing. Circularity: the chain is not circular - the donors carry their own experimental plasma-membrane evidence (human ADGRA2 has GO:0005886 EXP x3 plus IDA; mouse Adgra2 has EXP and IDA), and ADGRA1's own ortholog node independently places it at the postsynaptic density, which is plasma membrane. The term is also directly supported for ADGRA1 by surface labelling of HA-ADGRA1 in primary hippocampal neurons (PMID:41961591). ACCEPT. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1917943 SUPPORTS TRANSFER Recorded for provenance only. The donor set contains no ADGRA1 ortholog, which means no ortholog-strength inference is available on this row; the term survives on independent evidence, not on the transfer. MGI:MGI:1925810 SUPPORTS TRANSFER Recorded for provenance only. The donor set contains no ADGRA1 ortholog, which means no ortholog-strength inference is available on this row; the term survives on independent evidence, not on the transfer. PANTHER:PTN001738137 UNRESOLVED PANTHER internal tree node, not a protein UniProtKB:Q96PE1 SUPPORTS TRANSFER Recorded for provenance only. The donor set contains no ADGRA1 ortholog, which means no ortholog-strength inference is available on this row; the term survives on independent evidence, not on the transfer. ZFIN:ZDB-GENE-081104-363 SUPPORTS TRANSFER Recorded for provenance only. The donor set contains no ADGRA1 ortholog, which means no ortholog-strength inference is available on this row; the term survives on independent evidence, not on the transfer. ZFIN:ZDB-GENE-131003-2 SUPPORTS TRANSFER Recorded for provenance only. The donor set contains no ADGRA1 ortholog, which means no ortholog-strength inference is available on this row; the term survives on independent evidence, not on the transfer. Supporting Evidence: PMID:41961591 Neurons sparsely receiving HA-ADGRA1 overexpression displayed surface HA signals along both MAP2-labeled dendrites and AnkG-labeled axon initial segments, suggesting subcellular localization to both pre- and postsynaptic sites file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md **1 of 6** IBA donor tokens are ADGRA1 orthologs |
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The cautious parent, deliberately chosen by PAINT over GO:0007186, and supportable. Reason: Same node and same all-paralog donor set as the GO:0005886 row (PTN001738137; human ADGRA2 plus two zebrafish adgra2/adgra3). Worth recording that PAINT gave ADGRA1 this term and withheld GO:0007186 - i.e. it declined to commit the family node to G-protein coupling. That restraint was well judged at the time and is now vindicated in substance by PMID:41961591. ACCEPT; the term is true of a cell-surface 7-TM receptor that activates heterotrimeric G proteins. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001738137 UNRESOLVED PANTHER internal tree node, not a protein UniProtKB:Q96PE1 SUPPORTS TRANSFER All four non-node donors are ADGRA2/ADGRA3. Provenance note only; the term is generic enough that the paralog restriction does not threaten it. ZFIN:ZDB-GENE-081104-363 SUPPORTS TRANSFER All four non-node donors are ADGRA2/ADGRA3. Provenance note only; the term is generic enough that the paralog restriction does not threaten it. ZFIN:ZDB-GENE-131003-2 SUPPORTS TRANSFER All four non-node donors are ADGRA2/ADGRA3. Provenance note only; the term is generic enough that the paralog restriction does not threaten it. Supporting Evidence: file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md | `PANTHER:PTN001738137` | ADGRA1, ADGRA2, ADGRA3 | GO:0005886, GO:0007166 | |
| GO:0014069 postsynaptic density | IBA GO_REF:0000033 | ACCEPT | Summary: Genuine ortholog transfer: the sole protein donor is mouse Adgra1, which holds this exact term by IDA. Reason: Node PTN002914505 reaches exactly ADGRA1 among human genes, and its only non-node WITH/FROM token is MGI:MGI:1277167 = mouse Adgra1 (Q8C4G9, Swiss-Prot). QuickGO shows that donor carries GO:0014069 by IDA (and EXP) from PMID:28935861, which combined brain sub-cellular fractionation with super-resolution microscopy. The ACRV1 precision check therefore comes back NEGATIVE here: the propagation lands on the same term as the donor's IDA, not several levels above it, so no downward MODIFY is warranted. Recorded because a null result from a check is a finding. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1277167 SUPPORTS TRANSFER Single ortholog donor with its own IDA to the identical term; transfer is sound and maximally specific. PANTHER:PTN002914505 UNRESOLVED PANTHER internal tree node, not a protein Supporting Evidence: PMID:28935861 Using super-resolution microscopy on primary neuronal culture we confirmed the postsynaptic localization of PLEKHA5 and ADGRA1. |
| GO:0098978 glutamatergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: Ortholog transfer from mouse Adgra1's SynGO IDA; same node as GO:0014069. Reason: Node PTN002914505, donor MGI:MGI:1277167 = mouse Adgra1 (Q8C4G9), which holds GO:0098978 by IDA/EXP from PMID:28935861 curated by SynGO. Consistent with ADGRA1 being enriched in hippocampal PV interneurons, whose own excitatory inputs are glutamatergic, and with surface ADGRA1 puncta co-localising with pre- and postsynaptic markers. ACCEPT. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1277167 SUPPORTS TRANSFER Ortholog donor carrying the identical term by IDA. No precision loss. PANTHER:PTN002914505 UNRESOLVED PANTHER internal tree node, not a protein Supporting Evidence: PMID:28935861 Using super-resolution microscopy on primary neuronal culture we confirmed the postsynaptic localization of PLEKHA5 and ADGRA1. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Redundant ancestor of GO:0004930, which the gene holds and which is now supported. Reason: IPR017981 is the family-2 (secretin-like) 7-TM signature, so the inference is sound as far as it goes, but GO:0004888 is the parent of GO:0004930 and adds nothing once the child is held. PMID:41961591 supplies direct evidence at the child's level (Galpha13/11/15 activation), so the specific term is the right one to keep. This is a redundancy MODIFY, not a correction. Proposed replacements: G protein-coupled receptor activity Supporting Evidence: PMID:41961591 Full-length ADGRA1 activated several G proteins, most notably GΞ±13 |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Fold-derived, but the activity is now independently demonstrated. Reason: The G-protein-activating half of GO:0004930 is now demonstrated: TRUPATH BRET2 across all 14 Galphabetagamma sensors shows activation of Galpha13, Galpha11 and Galpha15 with a plasmid copy-number dependence and an unresponsive GalphaoB control (PMID:41961591). The assay used the MOUSE ortholog (Q8C4G9) overexpressed in HEK293T, so the appropriate evidence for the human gene is ISS with UniProtKB:Q8C4G9 as the supporting entity; GOA is asked to attach that evidence line to the existing term (see suggested_questions), since all four current lines cite references with no functional content. The term is therefore ACCEPTed and the reference problem recorded in reference_review rather than converted into a GO action. Caveat retained rather than smoothed over: the receptor is an orphan and the activation is agonist-independent, so the definition's first conjunct ('combining with an extracellular signal') is unestablished; that is raised as an ontology question, not acted on. Supporting Evidence: PMID:41961591 Full-length ADGRA1 activated several G proteins, most notably GΞ±13 PMID:41961591 GΞ±11, GΞ±15, and GΞ±13 all exhibited a plasmid copy-number-dependent change in BRET2, supporting the specificity of these measurements |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Consistent with the IBA row for the same term; supported. Reason: InterPro IPR017981 (family-2 7-TM) supports a cell-surface receptor signalling role, and PAINT independently assigns the same term. ACCEPT. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Now supported downstream of the demonstrated G-protein activation. Reason: GO:0007186 is defined as the series of molecular signals in which an activated receptor promotes GDP/GTP exchange on a heterotrimeric G-protein alpha subunit; PMID:41961591 demonstrates exactly that step for the mouse ortholog with three Galpha subtypes and a dose-response control. ACCEPT. Same caveat as GO:0004930: the definition's opening clause presumes a ligand, and ADGRA1 has none - raised as an ontology question rather than acted on. Supporting Evidence: PMID:41961591 GΞ±11, GΞ±15, and GΞ±13 all exhibited a plasmid copy-number-dependent change in BRET2, supporting the specificity of these measurements |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Root-level membrane term; the specific compartment is known. Reason: GO:0016020 is the ontology root for membrane and says nothing this gene's record does not already say better. ADGRA1 is a 7-TM receptor whose PAINT ortholog node places it at the postsynaptic density and glutamatergic synapse by transfer from mouse Adgra1 IDA, and surface-labelled HA-ADGRA1 forms puncta at the neuronal surface (PMID:41961591). GO:0005886 is supported and is the informative parent of those locations. This row derives from UniProtKB-SubCell:SL-0162, and UniProt's own SUBCELLULAR LOCATION for this entry is sequence-predicted (ECO:0000255) rather than observed, so nothing is lost by refining it. Proposed replacements: plasma membrane Supporting Evidence: file:human/ADGRA1/ADGRA1-uniprot.txt -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane |
| GO:0005515 protein binding | IPI PMID:24550280 Large-scale interaction profiling of PDZ domains through pro... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of DLG1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Proteomic peptide-phage display: the ADGRA1 C-terminal peptide was selected from a library of all human C-terminal peptides by a PDZ domain of DLG1. The interactor on the ADGRA1 side is the peptide, not the full-length receptor - a real caveat, but the peptide is precisely the PDZ-binding motif at issue. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:24550280 With these libraries we screened the nine PSD-95/Dlg/ZO-1 (PDZ) domains of human Densin-180, Erbin, Scribble, and Disks large homolog 1 for peptide ligands. file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of GRID2IP. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. GRID2IP contributes 2 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of MPDZ. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. MPDZ contributes 13 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of DLG4. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. DLG4 contributes 3 annotated PDZ domains, and IntAct records a best dissociation constant of 8.3 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of APBA1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. APBA1 contributes 2 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of TJP1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. TJP1 contributes 3 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of DLG1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. DLG1 contributes 3 annotated PDZ domains, and IntAct records a best dissociation constant of 4.6 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of IL16. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. IL16 contributes 4 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of SCRIB. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. SCRIB contributes 4 annotated PDZ domains, and IntAct records a best dissociation constant of 20.6 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of DLG2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. DLG2 contributes 3 annotated PDZ domains, and IntAct records a best dissociation constant of 7.9 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of PDZK1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. PDZK1 contributes 4 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of FRMPD2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. FRMPD2 contributes 3 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of MAGI2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. MAGI2 contributes 6 annotated PDZ domains, and IntAct records a best dissociation constant of 6.7 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of LNX2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. LNX2 contributes 4 annotated PDZ domains, and IntAct records a best dissociation constant of 11.7 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of PATJ. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. PATJ contributes 10 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of LNX1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. LNX1 contributes 4 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of DLG3. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. DLG3 contributes 3 annotated PDZ domains, and IntAct records a best dissociation constant of 9.8 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of MAGI1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. MAGI1 contributes 6 annotated PDZ domains, and IntAct records a best dissociation constant of 21.2 uM. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of APBA2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. APBA2 contributes 2 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of GRIP2. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. GRIP2 contributes 7 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of WHRN. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. WHRN contributes 3 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Uninformative 'protein binding' for a mechanistically defined interaction: ADGRA1's C-terminal class I PDZ-binding motif engaging a PDZ domain of GRIP1. Reason: ADGRA1's cytoplasmic C-terminus ends in ETTV, a class I PDZ-binding motif (consensus X-[ST]-X-[VIL]), on a 255-residue cytoplasmic tail (UniProt TOPO_DOM 306..560). Both references behind this gene's GO:0005515 rows are PDZ-specific assays by construction, all 21 partners carry annotated PDZ domains (2-13 each, all reviewed Swiss-Prot at canonical length), and IntAct curates the ADGRA1 side of every record as feature 'PDZ-binding motif' (sufficient to bind) against a partner 'PDZ domain'. 'protein binding' discards all of that; GO:0030165 states the mechanism. Quantitative holdup assay against a panel of human PDZ domains. GRIP1 contributes 7 annotated PDZ domains, and IntAct carries the kd:1(molar) placeholder for every record, i.e. the affinity fell below the assay's quantification threshold (~100-800 uM); the pair is nonetheless curated as a detected positive (negative flag False). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md 21/21 partners carry at least one annotated PDZ domain |
| GO:0004930 G protein-coupled receptor activity | NAS PMID:12565841 There exist at least 30 human G-protein-coupled receptors wi... | ACCEPT | Summary: Term correct; the cited reference is a genome-mining paper with no functional data (flagged MISCITED). Reason: The G-protein-activating half of GO:0004930 is now demonstrated: TRUPATH BRET2 across all 14 Galphabetagamma sensors shows activation of Galpha13, Galpha11 and Galpha15 with a plasmid copy-number dependence and an unresponsive GalphaoB control (PMID:41961591). The assay used the MOUSE ortholog (Q8C4G9) overexpressed in HEK293T, so the appropriate evidence for the human gene is ISS with UniProtKB:Q8C4G9 as the supporting entity; GOA is asked to attach that evidence line to the existing term (see suggested_questions), since all four current lines cite references with no functional content. The term is therefore ACCEPTed and the reference problem recorded in reference_review rather than converted into a GO action. Caveat retained rather than smoothed over: the receptor is an orphan and the activation is agonist-independent, so the definition's first conjunct ('combining with an extracellular signal') is unestablished; that is raised as an ontology question, not acted on. This particular reference is a database search that in fact singles ADGRA1 out as the family member LACKING the GPS domain, so it is the weakest possible basis for a receptor-activity call. NAS is nonetheless the correct evidence code for an author statement of this kind, so there is nothing malformed to fix. Supporting Evidence: PMID:12565841 All the novel receptors have a GPS domain in their N-terminus, except GPR123, as well as long Ser/Thr rich regions forming mucin-like stalks. |
| GO:0004930 G protein-coupled receptor activity | NAS PMID:17212699 The evolutionary history and tissue mapping of GPR123: speci... | ACCEPT | Summary: Term correct; the cited reference is an expression-mapping paper whose functional claim is explicitly a speculation (flagged MISCITED). Reason: The G-protein-activating half of GO:0004930 is now demonstrated: TRUPATH BRET2 across all 14 Galphabetagamma sensors shows activation of Galpha13, Galpha11 and Galpha15 with a plasmid copy-number dependence and an unresponsive GalphaoB control (PMID:41961591). The assay used the MOUSE ortholog (Q8C4G9) overexpressed in HEK293T, so the appropriate evidence for the human gene is ISS with UniProtKB:Q8C4G9 as the supporting entity; GOA is asked to attach that evidence line to the existing term (see suggested_questions), since all four current lines cite references with no functional content. The term is therefore ACCEPTed and the reference problem recorded in reference_review rather than converted into a GO action. Caveat retained rather than smoothed over: the receptor is an orphan and the activation is agonist-independent, so the definition's first conjunct ('combining with an extracellular signal') is unestablished; that is raised as an ontology question, not acted on. The cited paper is an in-situ hybridisation and real-time PCR expression map; its only functional statement is hedged as what GPR123 'may' do. Supporting Evidence: PMID:17212699 The CNS specific expression, together with the high sequence conservation between the vertebrate sequences investigated, indicate that GPR123 may have an important role in the regulation of neuronal signal transduction. |
| GO:0007165 signal transduction | NAS PMID:17212699 The evolutionary history and tissue mapping of GPR123: speci... | MODIFY | Summary: Redundant ancestor of a term the gene already holds by IBA and by IEA. Reason: GO:0007165 signal transduction is an ancestor of GO:0007166, which ADGRA1 holds twice already (IBA from PAINT, IEA from InterPro). The cited paper offers it only as a prediction from expression pattern and sequence conservation, with no assay. MODIFY to the informative descendant rather than REMOVE, since the essence is sound. Proposed replacements: cell surface receptor signaling pathway Supporting Evidence: PMID:17212699 The CNS specific expression, together with the high sequence conservation between the vertebrate sequences investigated, indicate that GPR123 may have an important role in the regulation of neuronal signal transduction. |
| GO:0016020 membrane | NAS PMID:12565841 There exist at least 30 human G-protein-coupled receptors wi... | MODIFY | Summary: Root-level membrane term; the specific compartment is known. Reason: GO:0016020 is the ontology root for membrane and says nothing this gene's record does not already say better. ADGRA1 is a 7-TM receptor whose PAINT ortholog node places it at the postsynaptic density and glutamatergic synapse by transfer from mouse Adgra1 IDA, and surface-labelled HA-ADGRA1 forms puncta at the neuronal surface (PMID:41961591). GO:0005886 is supported and is the informative parent of those locations. Proposed replacements: plasma membrane |
| GO:0016020 membrane | NAS PMID:17212699 The evolutionary history and tissue mapping of GPR123: speci... | MODIFY | Summary: Root-level membrane term; the specific compartment is known. Reason: GO:0016020 is the ontology root for membrane and says nothing this gene's record does not already say better. ADGRA1 is a 7-TM receptor whose PAINT ortholog node places it at the postsynaptic density and glutamatergic synapse by transfer from mouse Adgra1 IDA, and surface-labelled HA-ADGRA1 forms puncta at the neuronal surface (PMID:41961591). GO:0005886 is supported and is the informative parent of those locations. Proposed replacements: plasma membrane |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:15203201 The human and mouse repertoire of the adhesion family of G-p... | ACCEPT | Summary: Term correct, but this row is one of 25 identical block annotations from a family-catalogue paper (flagged MISCITED). Reason: The G-protein-activating half of GO:0004930 is now demonstrated: TRUPATH BRET2 across all 14 Galphabetagamma sensors shows activation of Galpha13, Galpha11 and Galpha15 with a plasmid copy-number dependence and an unresponsive GalphaoB control (PMID:41961591). The assay used the MOUSE ortholog (Q8C4G9) overexpressed in HEK293T, so the appropriate evidence for the human gene is ISS with UniProtKB:Q8C4G9 as the supporting entity; GOA is asked to attach that evidence line to the existing term (see suggested_questions), since all four current lines cite references with no functional content. The term is therefore ACCEPTed and the reference problem recorded in reference_review rather than converted into a GO action. Caveat retained rather than smoothed over: the receptor is an orphan and the activation is agonist-independent, so the definition's first conjunct ('combining with an extracellular signal') is unestablished; that is raised as an ontology question, not acted on. Provenance finding worth separating from the verdict: querying QuickGO by reference rather than by gene, PMID:15203201 carries 78 annotations across 27 distinct entities - GO:0016020 on 27, GO:0007186 on 26, GO:0004930 on 25 - i.e. essentially the whole human adhesion-GPCR family, all TAS, all assigned by GDB, from a paper that performed no perturbation on any of them. That is a block projection of family membership into a molecular function. It entered through GDB TAS, a route the ~April 2026 retirement of Swiss-Prot-keyword annotations did not touch, which is why this error class is still visible in GOA here. Supporting Evidence: PMID:15203201 EST expression charts for the entire repertoire of adhesion-GPCRs in human and mouse were established. file:human/ADGRA1/ADGRA1-bioinformatics/RESULTS.md `PMID:15203201` annotates **27 distinct entities** with identical evidence |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:15203201 The human and mouse repertoire of the adhesion family of G-p... | ACCEPT | Summary: Term now supported; row is part of the same 26-entity family block. Reason: The pathway step the term names - an activated receptor promoting GDP/GTP exchange on a Galpha subunit - is demonstrated for the mouse ortholog in PMID:41961591. ACCEPT. As with the GO:0004930 TAS row, the cited reference is a repertoire catalogue that carries this term on 26 adhesion GPCRs at once and contains no experiment; that is a provenance defect recorded in reference_review, not grounds to remove a term that is independently supported. Supporting Evidence: PMID:15203201 Currently the total number of human adhesion-GPCRs is 33. |
| GO:0016020 membrane | TAS PMID:15203201 The human and mouse repertoire of the adhesion family of G-p... | MODIFY | Summary: Root-level membrane term; the specific compartment is known. Reason: GO:0016020 is the ontology root for membrane and says nothing this gene's record does not already say better. ADGRA1 is a 7-TM receptor whose PAINT ortholog node places it at the postsynaptic density and glutamatergic synapse by transfer from mouse Adgra1 IDA, and surface-labelled HA-ADGRA1 forms puncta at the neuronal surface (PMID:41961591). GO:0005886 is supported and is the informative parent of those locations. This row is one of 27 identical GO:0016020 TAS annotations that PMID:15203201 carries across the adhesion-GPCR family. Proposed replacements: plasma membrane |
| GO:0098982 GABA-ergic synapse | ISS PMID:41961591 The atypical adhesion GPCR ADGRA1 controls hippocampal inhib... | NEW | Summary: Proposed: the cellular-component half of the same 2026 evidence that supports the GO:0032230 row - the receptor is at the inhibitory synapse. Reason: GOA places ADGRA1 only at the glutamatergic synapse and postsynaptic density, both by IBA from a 2017 sub-cellular proteomics survey. The 2026 study localises it directly at the INHIBITORY synapse: HA-ADGRA1 delivered ex vivo to the dentate gyrus of PV-Cre and SST-Cre mice co-localises with vGAT, the vesicular GABA transporter. Without this term the review asserts a molecular function at the glutamatergic postsynapse while asserting positive regulation of GABAergic transmission as the process, and the compartment and the process do not line up. Same reference, same organism, same strength as the GO:0032230 row, so the same evidence code: ISS from mouse Adgra1 (Q8C4G9). This is additive - the existing GO:0098978 ACCEPT is left alone, deferring to the SynGO curator, and the two terms are not mutually exclusive for a receptor found at a subset of synapses of both kinds. GO:0098793 presynapse was considered and DECLINED: the only statement supporting it is hedged ('suggesting subcellular localization'), it rests entirely on overexpressed HA-tagged receptor because no reliable antibody exists, and the paper's own functional controls argue against the presynaptic release apparatus being where the receptor acts - paired-pulse ratio and coefficient of variation are unchanged and Syt2-labelled PV terminal density is unaltered. Recorded as a knowledge gap instead. Supporting Evidence: PMID:41961591 HA-ADGRA1 localized with inhibitory vGAT slightly higher in PV+ neurons than in SST+ neurons PMID:41961591 Surface ADGRA1 formed puncta that partially co-localized with both pre- and postsynaptic markers |
| GO:0032230 positive regulation of synaptic transmission, GABAergic | ISS PMID:41961591 The atypical adhesion GPCR ADGRA1 controls hippocampal inhib... | NEW | Summary: Proposed: ADGRA1 is required in PV interneurons for normal inhibitory synaptic strength onto dentate gyrus granule cells. Reason: Conditional deletion of Adgra1 in parvalbumin interneurons reduces inhibitory synaptic strength onto dentate gyrus granule cells and impairs PV intrinsic excitability, so the receptor positively regulates GABAergic synaptic transmission. The perturbation is in mouse, hence ISS for the human gene with UniProtKB:Q8C4G9 as the supporting entity. This is currently ADGRA1's only functional biological process supported by a perturbation of any kind, and it sits on the same mouse gene that seeds PAINT node PTN002914505 - so it is also the obvious candidate for PAINT to propagate. Supporting Evidence: PMID:41961591 ADGRA1 deletion in PV interneurons impairs intrinsic excitability and reduces inhibitory synaptic strength onto dentate gyrus granule cells. |
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Download this section (compressed HTML)Q: For PAINT. Node PTN002914505 has a human reach of exactly ADGRA1 and gives it only GO:0014069 and GO:0098978, both from a 2017 proteomics survey; ADGRA1 consequently receives no molecular function and no functional biological process from the tree at all. Its sole donor, MGI:MGI:1277167 (mouse Adgra1), now carries direct G-protein coupling data and a parvalbumin-interneuron conditional-knockout phenotype from PMID:41961591. Would GO_Central consider adding GO:0004930 and a GABAergic synaptic-transmission term at that node? It would give ADGRA1 orthologs across vertebrates their first mechanism term in one edit.
Suggested experts: GO_Central PAINT curators, PANTHER
Q: For GOA. PMID:15203201, a catalogue of the human and mouse adhesion-GPCR repertoire with EST expression charts and no perturbation experiment, carries 78 TAS annotations from GDB across 27 distinct entities: GO:0016020 on 27, GO:0007186 on 26, GO:0004930 on 25 - essentially the whole family. This is the 'structural class became a molecular function' pattern that the retirement of Swiss-Prot-keyword annotations was expected to have removed from GO; it survives because it entered via GDB TAS rather than via UniProtKB-KW. The terms are defensible for ADGRA1 on independent 2026 evidence, but that will not be true of all 25 recipients. Is a review of this reference's block warranted?
Suggested experts: GOA curators, GO Consortium
Q: For UniProt (Q86SQ6). Four corrections, none of which has a GO row to act on. (1) CC FUNCTION reads only 'Orphan receptor'; the entry predates PMID:41961591 (Galpha13/11/15 coupling of the mouse ortholog) and PMID:36115835 (21 PDZ partners with measured affinities). (2) There is no FT MOTIF feature for the C-terminal class I PDZ-binding motif at residues 557-560 (ETTV), even though the entry's own CC INTERACTION block lists 21 PDZ-domain proteins and the motif has been predicted in the literature since 2007. (3) CC SUBCELLULAR LOCATION is 'Membrane {ECO:0000255}', sequence-predicted, while SynGO holds IDA postsynaptic-density and glutamatergic-synapse annotations on the mouse ortholog. (4) NbExp in the INTERACTION block counts PDZ domains assayed within one holdup dataset, not independent experiments - it equals the IntAct record count for 21 of 21 partners.
Suggested experts: UniProt curators
Q: For IntAct/GOA. The 21-partner GO:0005515 set for ADGRA1 is the subset of IntAct's 80 partners with two or more records, and because every record is one PDZ domain from the same holdup dataset, that filter selects multi-PDZ-domain scaffolds rather than strong binders. Thirteen of the 21 selected partners have no quantified affinity at all, while 23 partners with a measured Kd are excluded. The cleanest statement of the problem is a single pair: SNX27, at 3.7 uM the TIGHTEST binder measured anywhere in the dataset, is excluded, while DLG1 at 4.6 uM - the second tightest - is retained. Affinity is therefore not what separates them; PDZ-domain count is. Of the four tightest binders overall (SNX27 3.7, DLG1 4.6, MAST2 4.9, MAGI3 5.1 uM) three are excluded and only DLG1 is kept. Should an affinity-aware criterion be used where the source assay reports dissociation constants?
Suggested experts: IntAct curators, GOA curators
Q: Ontology question, raised rather than acted on. GO:0004930's definition requires 'combining with an extracellular signal and transmitting the signal across the membrane by activating an associated G-protein', and GO:0007186's begins 'initiated by a ligand binding to its receptor'. ADGRA1 satisfies the G-protein half and not the ligand half: it is an orphan, its activation is agonist-independent, and deleting its entire 19-residue ectodomain does not change the coupling profile. Is a definitional revision or a ligand-independent sibling term warranted for constitutively active and orphan receptors?
Suggested experts: GO ontology editors
Experiment: Measure G-protein coupling of the HUMAN receptor. Every coupling measurement to date used mouse Adgra1 (Q8C4G9); running the same TRUPATH BRET2 panel on human ADGRA1, and on the two alternative isoforms - especially Q86SQ6-1, whose ~800-residue Ser/Thr-rich N-terminal extension gives the receptor an ectodomain the canonical isoform lacks - would show whether agonist-independent Galpha13 activation is a property of the protein or of the short isoform.
Hypothesis: Human ADGRA1 couples to Galpha13 as the mouse ortholog does, and the long Ser/Thr-rich isoform Q86SQ6-1 behaves differently from the canonical ectodomain-less isoform.
Experiment: Test whether coupling is truly constitutive rather than an overexpression artefact. Titrate receptor density against BRET2 response alongside a known constitutively active GPCR and a known ligand-gated one, and repeat in neurons at near-endogenous expression using a knock-in tag, since the current result comes from HEK293T overexpression scored against empty vector.
Hypothesis: The agonist-independent G-protein activation reported for ADGRA1 is genuine constitutive activity rather than a consequence of receptor overexpression.
Experiment: Give the PDZ motif a phenotype. Deleting it changes neither synaptic localisation nor Galpha13 co-localisation, so the informative experiment is a knock-in ETTV-to-ETTA mouse assayed for the published PV-interneuron readouts - intrinsic excitability and inhibitory synaptic strength onto dentate gyrus granule cells - rather than another localisation assay.
Hypothesis: The C-terminal PDZ-binding motif has a function in inhibitory synaptic physiology even though it is dispensable for synaptic localisation.
Experiment: Identify which PDZ partners are engaged in vivo. Holdup measures affinity between isolated domains and a peptide; a proximity-labelling or co-immunoprecipitation experiment from parvalbumin interneurons would show which of DLG1-4, MAGI1/2, SCRIB, SNX27 and MAST2 the full-length receptor actually meets. SNX27 and MAST2 are worth including despite being absent from GOA, since they are the tightest binders measured.
Hypothesis: Only a subset of the PDZ-domain proteins that bind the ADGRA1 peptide in vitro engage the full-length receptor in parvalbumin interneurons.
Experiment: Raise an antibody that detects endogenous ADGRA1. The 2026 study states it could not determine endogenous localisation for lack of one, so every localisation result for this protein rests either on tagged overexpression or on mass spectrometry of fractionated brain.
Hypothesis: Endogenous ADGRA1 can be localised directly, testing whether the tagged-overexpression and fractionation results reflect where the native protein is.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether ADGRA1 sits on the presynaptic or the postsynaptic side of the inhibitory synapse is unresolved. Two distinct questions are involved and the evidence bears on them unequally. On LOCALISATION, the only positive statements are that tagged receptor appears on dendrites and on axon initial segments and co-localises with vGAT - and that sentence is hedged ('suggesting subcellular localization'), rests entirely on overexpressed HA-tagged protein because no reliable antibody exists, and the rescue result establishes which CELL the receptor is needed in rather than which side of the synapse it occupies. Those are the grounds on which GO:0098793 presynapse was considered and not proposed. Separately, on FUNCTION, paired-pulse ratio, coefficient of variation and Syt2-labelled terminal density are all unaltered, so whatever the receptor does, it is not acting through presynaptic release probability or terminal number. That is a mechanistic gap in its own right and is not evidence about where the protein is.
BIOLOGY
What is known: Known: the receptor is at inhibitory synapses (vGAT co-localisation) and is required in PV cells for their inhibitory output. Unknown: which side of the synapse the protein occupies, and by what mechanism a receptor that does not change release probability reduces inhibitory strength. Every localisation result rests on overexpressed tagged protein, because no reliable antibody exists.
Provenance (the field's own admissions):
Gap: No agonist is known for ADGRA1, and unlike every other adhesion GPCR it cannot use the tethered-agonist mechanism, because it has no GAIN domain and only a 19-residue extracellular N-terminus. The one experiment that tested whether that segment matters found it dispensable for basal G-protein activation, so how the receptor is switched on - or whether it is constitutively active and controlled only by where it is - is unresolved.
BIOLOGY
What is known: Known: the receptor activates Galpha13/11/15 when overexpressed, and deleting residues 1-22 does not change that. Unknown: whether any extracellular or membrane-embedded ligand exists, and whether coupling in neurons is regulated at all.
Provenance (the field's own admissions):
Gap: The C-terminal PDZ-binding motif binds at least 21 scaffold proteins with measurable affinity, yet its cellular job is unidentified: deleting it changes neither synaptic localisation nor co-localisation with Galpha13. Which of the PDZ partners the receptor actually engages in a parvalbumin interneuron, and what that engagement does, is open.
BIOLOGY
What is known: Known: the motif exists, is conserved, and binds DLG1-4, MAGI1/2, SCRIB and others in vitro at 4.6-116 uM. Known negative: it is not required for synaptic targeting. Unknown: any in vivo consequence of the motif.
Provenance (the field's own admissions):
Gap: Almost every functional fact about ADGRA1 comes from mouse. The only experiments on the human protein are an RNAi study in pluripotent stem cells, whose readouts are pleiotropic and isolate no molecular function, and two in vitro PDZ-domain binding datasets. There is no human electrophysiology, no human G-protein coupling measurement and no antibody able to detect the endogenous protein in either species.
BIOLOGYCURATION
What is known: Known: human C-terminal peptide binds human PDZ domains; human protein is detected by mass spectrometry (UniProt PE 1). Unknown: whether human ADGRA1 couples to Galpha13, and where the endogenous protein is.
Provenance (the field's own admissions):
Gap: PAINT gives ADGRA1 no molecular function and no functional biological process. Node PTN002914505, whose human reach is exactly ADGRA1, carries only two cellular-component terms, both traceable to a 2017 sub-cellular proteomics survey. The 2026 functional work on mouse Adgra1 - the very gene behind that node's only donor, MGI:MGI:1277167 - has not yet reached the tree.
CURATION
What is known: Known: the node exists, is correctly scoped to ADGRA1 orthologs, and already uses mouse Adgra1 as its donor. Unknown to PAINT: that the same donor now carries G-protein coupling data and a conditional-knockout synaptic phenotype.
Provenance (the field's own admissions):
Gap: GO:0004930 and GO:0007186 both presuppose a ligand in their definitions ('combining with an extracellular signal'; 'initiated by a ligand binding to its receptor'), and GO offers no ligand-free sibling. Orphan and constitutively active receptors such as ADGRA1 are therefore annotated to terms whose first clause is unestablished for them.
ONTOLOGY
What is known: Known: the GDP/GTP-exchange half of both definitions is demonstrated for ADGRA1. Unknown/absent: any GO term expressing receptor-driven G-protein activation without a ligand-reception step.
Provenance (the field's own admissions):
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