AP1S1 encodes sigma1A, the small subunit of adaptor protein complex 1 (AP-1), the clathrin adaptor that sorts transmembrane cargo between the trans-Golgi network and endosomes. AP-1 is a heterotetramer of two large chains (gamma and beta1), a medium chain (mu1) and a small chain (sigma1); in humans the gamma, mu1 and sigma1 positions are each filled by one of several paralogs, and sigma1A is the ubiquitously expressed member of the sigma1 set, with sigma1B and sigma1C showing more restricted expression. The complex is recruited to membranes by Arf1-GTP together with phosphatidylinositol 4-phosphate, which unlocks it into a cargo-binding conformation, and it then links selected membrane proteins to the clathrin lattice. Within the complex, sigma1A is not an inert structural filler. Cargo is selected through two classes of cytosolic sorting signal that bind different parts of AP-1: tyrosine-based YxxO motifs bind the mu1 subunit, while acidic dileucine motifs bind neither subunit alone but a composite site formed by the gamma and sigma1 chains together. sigma1A supplies the hydrophobic pockets of that site, and a solved AP-1 structure shows a dileucine-mimicking viral peptide bound directly in a pocket on sigma1. Substitutions at the sigma1A pocket residues abolish signal binding, and sigma1A is also required for the complex to assemble and to associate with TGN and endosomal membranes at all. Cargoes routed this way include the copper-transporting ATPases ATP7A and ATP7B, the lysosomal membrane protein LIMP-II, tyrosinase en route to maturing melanosomes, and basolaterally sorted proteins in polarized epithelia; HIV-1 Nef and Vpu subvert the same site to redirect host immune receptors. Loss of sigma1A function causes MEDNIK syndrome (also called IDEDNIK), an autosomal recessive multisystem disorder combining intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratodermia, together with a distinctive copper metabolism defect that mixes features of Menkes and Wilson diseases. Truncating, splice-site and missense alleles all converge on the same mechanism: failure of sigma1A to assemble into AP-1 and to recognise dileucine cargo. Knockdown in zebrafish disrupts skin formation, pigmentation and spinal neural network development and is rescued by wild-type but not truncated human AP1S1, and knockout in intestinal epithelial cells mislocalises tight-junction proteins and breaks the epithelial barrier.
Definition: Binding to an acidic dileucine sorting signal, a short peptide motif of the form acidic residue - X - X - X - Leu - Leu/Ile in the cytosolic tail of a transmembrane protein, which directs that protein into clathrin-coated carriers at the trans-Golgi network, endosomes or the plasma membrane.
Justification: GO can express the tyrosine-based branch of clathrin-adaptor cargo recognition through GO:0089710 endocytic targeting sequence binding, whose definition requires an essential tyrosine and internalization by clathrin-coated pits, but it has no counterpart for the dileucine branch. Searches of QuickGO for 'dileucine', 'sorting signal binding', 'targeting sequence binding' and 'leucine motif binding', and enumeration of the molecular-function children of GO:0140312 cargo adaptor activity, return nothing that fits. The consequence is that a well-characterised, subunit-attributable activity -- demonstrated by yeast three-hybrid, in vitro binding, point mutagenesis and X-ray crystallography, and destroyed by a human disease variant -- can currently only be annotated through GO:0035615 clathrin-cargo adaptor activity, a complex-level term whose own definition restricts it to the formation of endocytic vesicles. The term would apply to the sigma and large subunits of AP-1, AP-2 and AP-3 across eukaryotes. On the choice of parent: GO:0005515 protein binding is normally a term to avoid, and it is used here deliberately rather than by default. GO:0089710, the tyrosine counterpart this proposal is explicitly modelled on, is itself is_a GO:0005515 (is_a ancestors GO:0005515, GO:0005488, GO:0003674), so mirroring it places the two motif-binding siblings in the same genus. The obvious alternative, GO:0005048, was checked and rejected on parentage rather than on its name: its complete is_a ancestor set is itself plus GO:0003674, so it hangs directly off the molecular_function root with no binding ancestor at all -- neither GO:0005488 nor GO:0005515 -- and cannot serve as a genus for a binding activity. Its name is worth flagging because it is a trap: GO currently labels it 'signal sequence receptor activity' and carries 'signal sequence binding' only as a narrow synonym, while its definition still opens 'Binding to a signal sequence'. Name, synonym and definition therefore disagree with each other, which is exactly why the decision here rests on the is_a closure instead of on any of the three. If GO were to introduce a grouping term for sorting-signal binding, both GO:0089710 and this term should move under it together.
Parent term: protein binding
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-421831 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'trans-Golgi Network Coat Assembly'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-421833 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-421835 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'trans-Golgi Network Vesicle Scission'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-432706 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'trans-Golgi Network Lysosome Vesicle Destined Membrane Coat Assembly'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-432707 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'trans-Golgi Network Lysosomal Vesicle Scission'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-432712 | ACCEPT | Summary: sigma1A is on the Golgi membrane as part of the AP-1 coat; this row is the Reactome step 'Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture On Lysosome Vesicle Destined Golgi Membrane'. Reason: The Golgi membrane is where AP-1 assembles and where sigma1A therefore sits. UniProt records the protein on the cytoplasmic face of Golgi-derived coated vesicles from direct evidence, and AP-1 recruitment to that membrane is the Arf1-GTP/PI4P-dependent step these Reactome reactions model. sigma1A is not a passenger in this: in cells lacking all three sigma1 isoforms, wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes and the MEDNIK L90P variant does not, so the small subunit is required for the coat to be there at all. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as correct and core, but the six Golgi-membrane rows are six steps of one coat-assembly pathway and should be read as a single line of evidence. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0005765 lysosomal membrane | NAS PMID:23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiqui... | KEEP AS NON CORE | Summary: Statement-level placement of AP-1 on the lysosome-related-organelle route, from a Rab32/Rab38 review. Reason: The lysosomal membrane is a destination of AP-1-derived carriers rather than a place AP-1 works: the review describes AP-1 acting with BLOC-2 and AP-3 on early/recycling endosome tubules, from which cargo is delivered onward to lysosome-related organelles. The coat itself is shed before arrival. The claim is also entirely complex-level and NAS -- nothing in the paper concerns sigma1A specifically, and QuickGO returns 178 annotations over 48 distinct gene products for this one reference, which is the signature of a broad review projection. Real but peripheral, so retained as non-core rather than removed. Supporting Evidence: PMID:23247405 BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. PMID:23247405 Rab32 and Rab38 interact with AP-1, AP-3 and BLOC-2 on early/recycling endosome tubules, where cargo such as tyrosinase and Tyrp1 are loaded into vesicles or transport intermediates. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-432688 | KEEP AS NON CORE | Summary: Reactome places the AP-1 coat on the lysosome-directed carrier ('trans-Golgi Network Derived Lysosomal Vesicle Uncoating'). Reason: AP-1 packages cargo into carriers that reach the lysosome, so the association is real, but it is transient and terminal: the coat is shed at or before delivery, and the compartment where sigma1A actually functions is the TGN/endosome system. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Kept as a genuine but peripheral location. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-432707 | KEEP AS NON CORE | Summary: Reactome places the AP-1 coat on the lysosome-directed carrier ('trans-Golgi Network Lysosomal Vesicle Scission'). Reason: AP-1 packages cargo into carriers that reach the lysosome, so the association is real, but it is transient and terminal: the coat is shed at or before delivery, and the compartment where sigma1A actually functions is the TGN/endosome system. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Kept as a genuine but peripheral location. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. |
| GO:0005769 early endosome | NAS PMID:23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiqui... | ACCEPT | Summary: sigma1A-containing AP-1 acts on early/recycling endosomes as well as at the TGN. Reason: Unlike the lysosomal-membrane row from the same reference, this one names a compartment where AP-1 demonstrably works rather than one it delivers to. The endosome is half of AP-1's stated remit, and the statement is specific to the sigma1A-containing complex: the ubiquitous AP-1-sigma1A complex sorts between the TGN and early endosomes. It is also where the AP-1 rescue experiment reads out -- wild-type sigma1A restores gamma1 staining on TGN/endosomal membranes. Accepted as a core location despite the weak NAS evidence code, because stronger evidence for the same claim exists elsewhere. Supporting Evidence: PMID:23247405 Rab32 and Rab38 interact with AP-1, AP-3 and BLOC-2 on early/recycling endosome tubules, where cargo such as tyrosinase and Tyrp1 are loaded into vesicles or transport intermediates. PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localisation of AP1S1 to the Golgi apparatus (HPA). Reason: The strongest positional evidence on the human gene and entirely consistent with everything else: UniProt records Golgi apparatus from direct experimental evidence, and the protein sits on the cytoplasmic face of Golgi-derived coated vesicles. Core. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi apparatus transferred from the UniProt subcellular-location vocabulary. Reason: A faithful vocabulary mapping of a curated, experimentally supported UniProt location rather than a prediction: SL-0132 is UniProt's Golgi apparatus term and its GO mapping is GO:0005794 exactly. The underlying UniProt statement carries ECO:0000269 direct experimental evidence from PMID:9733768, and the same conclusion is reached independently by the HPA immunofluorescence row. Correct and core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0132 Β· UniProt subcellular location SL-0132, Golgi apparatus SUPPORTS TRANSFER Verified against the UniProt locations API: SL-0132 is 'Golgi apparatus' and maps to GO:0005794. The AP1S1 record asserts this location with ECO:0000269|PubMed:9733768, so the vocabulary step transfers a curated experimental statement, not an inference. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-182263 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Degradation of MHC I Complex'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-182279 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Formation of MHC I:Nef:AP-1:PACS-1 Complex'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-182286 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Transport of MHC I:Nef:AP-1:PACS-1 Complex'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2130619 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'TGN-lysosomal vesicle coat assembly'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2213236 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'TGN-lysosome vesicle uncoating and release of nonameric complex to lysosome'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-421833 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-421836 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'trans-Golgi Network Derived Vesicle Uncoating'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-432688 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'trans-Golgi Network Derived Lysosomal Vesicle Uncoating'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-432712 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture On Lysosome Vesicle Destined Golgi Membrane'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8951498 | KEEP AS NON CORE | Summary: Reactome models the uncoated/unassembled AP-1 pool as cytosolic; this row is the step 'Dissociation of Arf1:GDP, AP-1 Clathrin coated nonameric complex'. Reason: True but not where the protein does its job. AP-1 is a peripheral membrane complex that cycles on and off membranes -- UniProt classes sigma1A as a peripheral membrane protein on the cytoplasmic side -- so a soluble cytosolic pool genuinely exists between rounds of coat assembly. Several of these Reactome steps are explicitly the uncoating or dissociation half of that cycle, which is precisely when the complex is cytosolic and precisely when it is not functioning. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Retained as non-core: the informative locations are the Golgi, TGN and endosomal membranes annotated separately. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000044 | ACCEPT | Summary: Clathrin-coated pit, from the UniProt subcellular-location vocabulary. Reason: This looks like the same plasma-membrane error as the receptor-mediated endocytosis row and is not, which is why it has to be decided from the definition rather than the label. GO:0005905 is defined as an invagination of a membrane on which a clathrin coat forms, and the definition explicitly extends the compartment beyond the cell surface: coated pits form on the plasma membrane, 'in the trans-Golgi network, and on some endosomes'. TGN coated pits are exactly where AP-1 and therefore sigma1A act, and UniProt records 'Membrane, clathrin-coated pit' for this protein from direct experimental evidence. SL-0069 maps to GO:0005905 exactly. Correct as annotated. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0069 Β· UniProt subcellular location SL-0069, Clathrin-coated pit SUPPORTS TRANSFER Verified against the UniProt locations API: SL-0069 is 'Clathrin-coated pit', mapping to GO:0005905. The AP1S1 record carries this location with ECO:0000269|PubMed:9733768. The GO definition admits TGN and endosomal coated pits, so the transfer does not smuggle in a plasma-membrane claim. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the clathrin adaptor small-chain conserved site. Reason: IPR000804 is the conserved site shared by clathrin-adaptor small chains, and its GO mapping set is GO:0006886, GO:0016192 and GO:0030117 -- all three of which are exactly what any AP-complex sigma subunit does. Moving transmembrane proteins between the TGN, endosomes and the cell surface is intracellular protein transport by definition. The term is general, but generality is appropriate here because the signature is shared across AP-1, AP-2, AP-3 and AP-4 sigmas, which act in different compartments; a more specific term at this level would over-reach. Correct. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000804 Β· InterPro IPR000804, Clathrin adaptor complex, small chain (conserved site) SUPPORTS TRANSFER Confirmed via the InterPro API: a conserved_site entry whose GO mappings are GO:0006886, GO:0016192 and GO:0030117. AP1S1 carries this signature (PROSITE PS00989 CLAT_ADAPTOR_S on the UniProt record), and the mapped process is true of every member, so the mapping is sound rather than merely permitted. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:9733768 Identification and characterization of novel clathrin adapto... | REMOVE | Summary: Asserts AP1S1 acts in receptor-mediated endocytosis. AP-1 is not an endocytic adaptor and the cited paper contains no endocytosis experiment. Reason: The GO definition is explicit that this is a cell-surface process: a receptor on the cell surface binds ligand and 'the plasma-membrane region containing the receptor-ligand complex then undergoes endocytosis'. AP-1 does not work at the plasma membrane. Its recruitment is Arf1-GTP- and PI4P-dependent at the TGN, and the current statement of its remit is sorting between the TGN and endosomes plus polarized sorting to the basolateral and somatodendritic domains -- never internalisation from the cell surface. The adaptor that does clathrin-mediated endocytosis is AP-2, whose small subunit is the paralog AP2S1, and the dileucine work makes the division of labour concrete by testing AP-1 and AP-2 hemicomplexes as distinct entities. The cited paper supports none of it: it is a gamma2-adaptin identification study whose sigma1A content is a yeast two-hybrid interaction and whose localisation result is paranuclear, non-overlapping with gamma1-adaptin. This is a traceable author statement, not an experimental annotation by a curator who read an assay we cannot see, so deferring to it is not required; and the argument here is a positive biological one about compartment, not an inference from the abstract being about another gene. The same paper's other row, AP-1 complex membership, is accepted -- that claim it does support. Supporting Evidence: PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:15377783 TGN localization of AP-1 depends on the small GTPase, Arf1, and the phosphoinositide, PI-4-P. PMID:9733768 Immunofluorescence microscopy analysis has revealed that gamma2-adaptin is localized to paranuclear vesicular structures that are not superimposed on structures containing gamma1-adaptin. PMID:17360967 the gamma/sigma1 or alpha/sigma2 hemicomplexes bound the dileucine-based motifs of several proteins quite strongly, whereas binding by the beta1/mu1 and beta2/mu2 hemicomplexes, and the individual beta or mu subunits, was extremely weak or undetectable. |
| GO:0009615 response to virus | IEP PMID:16548883 Transcriptomic and proteomic analyses of rhabdomyosarcoma ce... | MARK AS OVER ANNOTATED | Summary: AP1S1 transcript changed in one enterovirus 71 microarray; no functional follow-up. Reason: The evidence is an expression change in a single infection screen of a single rhabdomyosarcoma cell line, in which 191 transcripts moved more than twofold. AP1S1 is not named anywhere in the abstract; UniProt's INDUCTION line is the traceable statement. IEP evidence supports 'the transcript responds to virus', whereas the annotation claims involvement in the response, and nothing in the paper tests whether AP1S1 does anything during infection. The reference projects to 20 distinct gene products in QuickGO, all on the same footing. Not wrong enough to remove -- the observation is real and reproducible -- but it is an unvalidated screen hit and should not be read as a function. Note that AP-1 does have genuine, mechanistic virus biology (HIV-1 Nef and Vpu both hijack the gamma1-sigma1A dileucine site), but that is a different claim, supported by different papers, and is captured elsewhere in this review rather than by this row. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71) infection. PMID:16548883 Using Acuity software and LOWESS normalization, 152 genes were found to be downregulated while 39 were upregulated by greater than twofold. |
| GO:0015031 protein transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the AP-complex sigma-subunit family. Reason: IPR016635 is the family-level entry for AP-complex sigma subunits and maps to exactly one term, GO:0015031. That is the correct least-committal statement for a signature shared by AP-1, AP-2, AP-3 and AP-4 sigmas, which move proteins in different compartments. True of AP1S1 and redundant with, but consistent with, the more specific intracellular-protein-transport row. Accepted as a correct if uninformative parent. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR016635 Β· InterPro IPR016635, Adaptor protein complex, sigma subunit (family) SUPPORTS TRANSFER Confirmed via the InterPro API: a family entry mapping to GO:0015031 alone. AP1S1 is a member (PIRSF015588 on the UniProt record). Deliberately generic because the family spans four AP complexes; that breadth is the reason the term is a parent rather than a failure of the mapping. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: AP1S1 peptide detected in a bulk NK-cell membrane-fraction proteome. Reason: The claim is true -- sigma1A is a peripheral membrane protein on the cytoplasmic face of coated vesicles, so it is expected in a membrane fraction -- but the annotation carries almost no information. GO:0016020 is a root-level compartment, and the assay cannot say which membrane; the authors themselves note that a large share of what they recovered are proteins merely transiently associated with membranes, which is exactly sigma1A's situation. The projection is total: this single reference yields 1142 annotations across 1142 distinct gene products in QuickGO, i.e. one per protein identified. Retained because it is not false, but the informative locations are the Golgi, TGN, cytoplasmic-vesicle and coated-pit rows. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores. PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. |
| GO:0016192 vesicle-mediated transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of vesicle-mediated transport from the pan-AP-sigma ancestral node PTN000204281 of PANTHER family PTHR11753. Correct, and correctly general. Reason: The tempting review here is that vesicle-mediated transport is vague when AP-1 does something far more specific, and that the row should be modified to a TGN-to-endosome sorting term. That would be wrong, and the reason is visible once the node is resolved rather than the donor count read. Each of the eleven gene-level donors was resolved individually, and they are not a set of AP-1 orthologs: they comprise AP-1 sigmas (mouse Ap1s1 and Ap1s2, fly AP-1sigma, budding-yeast Aps1, fission-yeast vas2), AP-2 sigmas (human AP2S1, rat Ap2s1, fly AP-2sigma, worm aps-2) and AP-3 sigmas (budding-yeast Aps3, C. albicans Aps3). Those subunits work in different compartments and different pathways -- TGN/endosome sorting, clathrin-mediated endocytosis at the plasma membrane, and lysosome/LRO delivery respectively. The donors therefore do not agree on a pathway, and vesicle-mediated transport is precisely their least common ancestor. A compartment-specific term placed at this node would propagate AP-1 biology onto every AP-2 and AP-3 sigma in the family, which is the failure the general term avoids. GRANULARITY_MISMATCH is explicitly not applicable: it requires that the donors agree and a more specific term was available, and neither holds. Separately, the target is unambiguously inside the inheriting clade -- its own 1:1 mouse ortholog Ap1s1 is among the donors -- and there is no evidence of loss or divergence: AP1S1 is a full-length 158-residue sigma with an intact longin-like fold, a solved structure inside the assembled AP-1 core, and a human loss-of-function disease phenotype that is a trafficking disease. The term is also genuinely core rather than merely defensible: moving cargo in coated vesicles is what this protein exists to do. Propagation Review Root cause: NO FAILURE CORE Sources checked: CGD:CAL0000182525 Β· APS3, Candida albicans AP-3 sigma subunit (UniProtKB:Q59QC5) SUPPORTS TRANSFER Resolved by UniProt xref lookup to Q59QC5, the C. albicans AP-3 sigma. Its own GO record carries GO:0006896 Golgi to vacuole transport by IMP (PMID:20870878), so it contributes independent experimental grounding -- from an AP-3, not AP-1, context, which is part of why the node's term is the shared parent. FB:FBgn0039132 Β· AP-1sigma, Drosophila melanogaster AP-1 sigma subunit SUPPORTS TRANSFER Resolved by UniProt xref lookup to the D. melanogaster AP-1sigma gene (four TrEMBL isoform entries, all 'AP complex subunit sigma'). An AP-1-clade donor, orthologous to the target's own subfamily. FB:FBgn0043012 Β· AP-2sigma, Drosophila melanogaster AP-2 sigma subunit SUPPORTS TRANSFER Resolved by UniProt xref lookup to the D. melanogaster AP-2sigma gene. An AP-2-clade donor. Present in this row's WITH/FROM; it appears in the node's GO:0043231 seed list in the fetched PAINT slice but not in that slice's GO:0016192 seed list, a routine difference between the slice snapshot (dated 20260828) and the current GOA release. MGI:MGI:1098244 Β· Ap1s1, Mus musculus sigma1A (UniProtKB:P61967), the 1:1 ortholog of the target SUPPORTS TRANSFER The most relevant donor: resolved to P61967, AP1S1_MOUSE, the direct mouse ortholog of this gene and the same subunit, which is what places the target squarely inside the clade that inherited the function. Its own GO:0016192 rows are weak taken alone -- a TAS to an AP-3 review (PMID:9714600) and a NAS (PMID:2040623) -- though it separately carries GO:0042147 retrograde transport by IMP (PMID:24928897). This donor's weight comes from orthology and subunit identity, not from the strength of its own process annotations. MGI:MGI:1889383 Β· Ap1s2, Mus musculus sigma1B (UniProtKB:Q9DB50) SUPPORTS TRANSFER Resolved to Q9DB50, the mouse sigma1B paralog. It carries GO:0016192 by IMP (PMID:24928897) and GO:0016182 synaptic vesicle budding by IDA (PMID:20203623) on its own record -- experimental grounding within the AP-1 sigma clade. PANTHER:PTN000204281 Β· PTHR11753 ADAPTOR COMPLEXES SMALL SUBUNIT FAMILY, ancestral IBD node SUPPORTS TRANSFER The node, not a donor. The fetched PAINT slice shows PTN000204281 carrying two IBD assertions: GO:0016192 (this one, 10 seeds in the slice) and GO:0043231 (13 seeds, including UniProtKB:P61966, the target itself -- though no GO:0043231 IBA row exists in this gene's GOA, so there is nothing to review for it). Because the seeds span AP-1, AP-2 and AP-3 sigma subunits across fungi, nematode, fly, rodent and human, the node is the deep pan-AP-sigma ancestor and vesicle-mediated transport is its correct least common ancestor term. AP1S1 descends from it. PomBase:SPAP27G11.06c Β· vas2, Schizosaccharomyces pombe AP-1 sigma-1 (UniProtKB:Q9P7N2) SUPPORTS TRANSFER Resolved to Q9P7N2, the fission-yeast AP-1 sigma. Independently grounded: GO:0042147 and GO:0099638 by IDA (PMID:19624755). Its presence makes the node at least as old as the animal/fungal divergence. RGD:620188 Β· Ap2s1, Rattus norvegicus AP-2 sigma (UniProtKB:P62744) SUPPORTS TRANSFER Resolved to P62744, the rat AP-2 sigma. Independently grounded by IDA/IMP/EXP rows for GO:0098884 (PMID:17289840). An AP-2-clade donor. SGD:S000003561 Β· APS3, Saccharomyces cerevisiae AP-3 sigma (UniProtKB:P47064) SUPPORTS TRANSFER Resolved to P47064, the budding-yeast AP-3 sigma, with GO:0006896 by IMP (PMID:9335339) on its own record. An AP-3-clade donor. SGD:S000004160 Β· APS1, Saccharomyces cerevisiae AP-1 sigma-1 (UniProtKB:P35181) SUPPORTS TRANSFER Resolved to P35181, the budding-yeast AP-1 sigma, with GO:0006896 by IMP (PMID:17003107). An AP-1-clade donor from the other yeast lineage. UniProtKB:P53680 Β· AP2S1, Homo sapiens AP-2 sigma SUPPORTS TRANSFER The human AP-2 sigma paralog, independently grounded for GO:0048488 synaptic vesicle endocytosis by IDA and IMP (PMID:11102472). Its inclusion is what makes the node pan-AP rather than AP-1-specific, and it is the structural anchor used in this review's bioinformatics analysis. WB:WBGene00000157 Β· aps-2, Caenorhabditis elegans AP-2 sigma (F02E8.3, UniProtKB:Q19123) SUPPORTS TRANSFER Not resolvable through UniProt xref search; recovered via the GO API bioentity endpoint, which returns 'AP complex subunit sigma', NCBITaxon:6239, synonyms CELE_F02E8.3 / F02E8.3, and the gene symbol aps-2. An AP-2-clade nematode donor. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. PMID:19057675 Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. file:human/AP1S1/AP1S1-bioinformatics/RESULTS.md All five verify. P61966 is at sequence version 1 and is 158 aa, matching the length asserted by the script. |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping of the same process from two signatures. Reason: Both signatures map to GO:0016192 and both are genuinely borne by this protein: the broad clathrin-adaptor small-chain conserved site and, more tellingly, the AP-1-specific sigma family entry. The conclusion is identical to the IBA's and correct for the same reasons. Duplication of a term across evidence codes is expected and not a defect. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000804 Β· InterPro IPR000804, Clathrin adaptor complex, small chain (conserved site) SUPPORTS TRANSFER GO mappings GO:0006886, GO:0016192, GO:0030117 per the InterPro API. Pan-AP signature, so a general process term is the right output. InterPro:IPR044733 Β· InterPro IPR044733, AP-1 complex subunit sigma (family) SUPPORTS TRANSFER GO mappings GO:0035615, GO:0016192, GO:0030121 per the InterPro API. This is the AP-1-sigma-specific family entry, matched by AP1S1 on its UniProt record, so it is a paralog-appropriate signature and not a family-wide over-call. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. |
| GO:0016192 vesicle-mediated transport | NAS PMID:23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiqui... | ACCEPT | Summary: Statement-level restatement of AP-1's transport role, from a Rab32/Rab38 review that discusses AP-1 as one of the machineries delivering cargo to lysosome-related organelles. Reason: The term is correct and core for AP1S1 -- this is what the protein does -- so the row is accepted even though its evidence is weak and complex-level. It adds nothing the IBA does not already carry with a considered phylogenetic judgment behind it, and neither reference says anything about sigma1A specifically. Kept rather than removed because duplicate terms across evidence codes are legitimate and the claim is true. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:23247405 BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. |
| GO:0016192 vesicle-mediated transport | NAS PMID:27057418 Role of the epithelial cell-specific clathrin adaptor comple... | ACCEPT | Summary: Statement-level restatement of AP-1's transport role, from a review of the epithelial AP-1B variant, whose subject is basolateral sorting from recycling endosomes. Reason: The term is correct and core for AP1S1 -- this is what the protein does -- so the row is accepted even though its evidence is weak and complex-level. It adds nothing the IBA does not already carry with a considered phylogenetic judgment behind it, and neither reference says anything about sigma1A specifically. Kept rather than removed because duplicate terms across evidence codes are legitimate and the claim is true. Supporting Evidence: PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:27057418 Sorting takes place at one of 2 major sorting stations in the cells, the trans-Golgi network (TGN) and recycling endosomes (REs). |
| GO:0030117 membrane coat | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane coat, from the clathrin-adaptor small-chain conserved site. Reason: GO:0030117 is defined to include coats 'formed by clathrin plus an adaptor complex', which is precisely AP-1 with clathrin. sigma1A is a constituent of that coat, not merely near it: it is one of the four chains in the crystallised AP-1 core and UniProt places it in the coat surrounding the cytoplasmic face of Golgi-derived coated vesicles. Correct and core. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000804 Β· InterPro IPR000804, Clathrin adaptor complex, small chain (conserved site) SUPPORTS TRANSFER GO:0030117 is one of this entry's three mappings per the InterPro API. Every member of the signature is a small chain of a membrane coat adaptor, so the mapping holds across the whole signature and specifically for AP1S1, whose membership in the AP-1 coat is structurally solved (PDB 4P6Z, chain S). Supporting Evidence: PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. PMID:15377783 The heterotetrameric adaptor proteins (AP complexes) link the outer lattice of clathrin-coated vesicles with membrane-anchored cargo molecules. |
| GO:0030121 AP-1 adaptor complex | IEA GO_REF:0000002 | ACCEPT | Summary: AP-1 adaptor complex membership, from the AP-1-specific sigma family signature. Reason: The GO term definition settles this without recourse to any paper: GO:0030121 is a heterotetramer of beta1, gamma, mu1 and sigma1 subunits, and the definition goes on to name the human isoforms explicitly, including sigma1A. AP1S1 is sigma1A. The signature used is the AP-1-sigma-specific family rather than the pan-AP one, so this is a paralog-appropriate mapping: it would not fire on AP2S1 or AP4S1. Independently confirmed by structure (sigma1 is one of the four chains of the crystallised AP-1 core, and PDB 4P6Z contains this exact protein as chain S over residues 1-158) and by co-immunoprecipitation of myc-sigma1A with endogenous gamma1. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044733 Β· InterPro IPR044733, AP-1 complex subunit sigma (family) SUPPORTS TRANSFER Confirmed via the InterPro API: a family entry, not a broad domain, whose GO mappings are GO:0035615, GO:0016192 and GO:0030121. Because it is restricted to AP-1 sigma subunits, the complex-membership mapping is specific rather than inherited from the wider adaptor-sigma family, and it agrees with the GO definition of GO:0030121, which names sigma1A. Supporting Evidence: PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. PMID:39269494 AP-1 consists of two large Ξ³ and Ξ²1 subunits, a medium-sized ΞΌ1 subunit, and a small Ο1 subunit file:human/AP1S1/AP1S1-uniprot.txt DR PDB; 4P6Z; X-ray; 3.00 A; S=1-158. |
| GO:0030121 AP-1 adaptor complex | NAS PMID:15377783 Crystal structure of the clathrin adaptor protein 1 core. | ACCEPT | Summary: AP-1 complex membership stated by the AP-1 core crystal structure paper. Reason: The evidence code understates this. The paper reports the crystal structure of the AP-1 core and states that the core comprises the two large-chain N-terminal fragments plus the intact medium and small chains, mu1 and sigma1 -- sigma1 is a crystallised component of the complex, not an inferred one. Core. Supporting Evidence: PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). |
| GO:0030121 AP-1 adaptor complex | NAS PMID:27057418 Role of the epithelial cell-specific clathrin adaptor comple... | ACCEPT | Summary: AP-1 complex membership stated in a review of the epithelial AP-1B variant. Reason: Correct, though the weakest of the four sources for this term: a review whose subject is the mu1B-containing AP-1B variant rather than the sigma subunit. sigma1A is present in both AP-1A and AP-1B, so the membership claim holds. Accepted as a redundant but true restatement of a term that is independently established by structure. Supporting Evidence: PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. PMID:27057418 Polarized sorting may involve epithelial cell-specific sorting adaptors like the AP-1B clathrin adaptor complex. |
| GO:0030121 AP-1 adaptor complex | TAS PMID:9733768 Identification and characterization of novel clathrin adapto... | ACCEPT | Summary: AP-1 complex membership from the paper that characterised sigma1A and sigma1B. Reason: Unlike the receptor-mediated endocytosis row taken from the same paper, this claim is one the paper actually makes and tests: it identifies sigma1A as the small chain of the AP-1 complex and shows by yeast two-hybrid that it interacts with gamma1-adaptin, the AP-1 large chain. It is also the paper behind UniProt's experimentally-evidenced localisation statements for this protein. Core. Supporting Evidence: PMID:9733768 Analysis using a yeast two-hybrid system has revealed that, similarly to gamma1-adaptin, gamma2-adaptin is capable of interacting not only with the sigma1 chain (called as sigma1A in this paper), the small chain of the AP-1 complex file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic vesicle membrane, from the UniProt subcellular-location vocabulary. Reason: A faithful vocabulary mapping of a curated experimental statement. SL-0089 is UniProt's 'Cytoplasmic vesicle membrane' term and maps to GO:0030659; the AP1S1 record asserts it with ECO:0000269 direct evidence and adds the mechanistically important detail that the protein is peripheral, on the cytoplasmic side -- which is exactly how a coat adaptor sits on a vesicle. Correct and core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0089 Β· UniProt subcellular location SL-0089, Cytoplasmic vesicle membrane SUPPORTS TRANSFER Verified against the UniProt locations API: SL-0089 maps to GO:0030659. The source statement on the AP1S1 record carries ECO:0000269|PubMed:9733768 and specifies peripheral association on the cytoplasmic side, consistent with coat adaptor topology. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. |
| GO:0030659 cytoplasmic vesicle membrane | TAS Reactome:R-HSA-421835 | ACCEPT | Summary: Reactome places AP-1 on the budded vesicle membrane ('trans-Golgi Network Vesicle Scission'). Reason: Correct: after scission the AP-1 coat remains on the cytoplasmic face of the newly formed carrier until uncoating, and UniProt records exactly this for sigma1A. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core; the vesicle membrane is a place sigma1A functions rather than merely visits. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. |
| GO:0030659 cytoplasmic vesicle membrane | TAS Reactome:R-HSA-421836 | ACCEPT | Summary: Reactome places AP-1 on the budded vesicle membrane ('trans-Golgi Network Derived Vesicle Uncoating'). Reason: Correct: after scission the AP-1 coat remains on the cytoplasmic face of the newly formed carrier until uncoating, and UniProt records exactly this for sigma1A. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core; the vesicle membrane is a place sigma1A functions rather than merely visits. Supporting Evidence: file:human/AP1S1/AP1S1-uniprot.txt CC the cytoplasmic face of coated vesicles located at the Golgi complex. file:human/AP1S1/AP1S1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Golgi apparatus {ECO:0000269|PubMed:9733768}. |
| GO:0032588 trans-Golgi network membrane | IEA GO_REF:0000117 | ACCEPT | Summary: TGN membrane from an ARBA machine-learned rule. Reason: The conclusion is right and, unusually for an ARBA row, the firing condition is traceable and genuinely met. Fetching the rule shows ten condition sets, each a FunFam-plus-taxon pair, all emitting the single annotation GO:0032588. The set that matches AP1S1 is FunFam 3.30.450.60:FF:000005 together with taxon Catarrhini; AP1S1 carries that FunFam on its UniProt record and is Catarrhini, so the rule fires legitimately rather than by a loose family match. The biology is independently solid: the TGN is AP-1's principal site of action. The one caveat worth recording is that the Catarrhini restriction is an artefact of how the rule was learned, not biology -- AP-1 localises to the TGN throughout eukaryotes, as the fission-yeast and budding-yeast members of this family show -- so the rule under-generalises rather than over-reaches, which is the harmless direction. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00033972 Β· ARBA rule ARBA00033972 SUPPORTS TRANSFER Fetched from the UniProt ARBA API: 10 condition sets over 16 distinct FunFams and 9 taxa, emitting only GO:0032588. Condition set 8 -- FunFam 3.30.450.60:FF:000005 AND taxon Catarrhini -- is the one AP1S1 satisfies, and it does satisfy both halves. A heterogeneous rule, but correctly applied here. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not |
| GO:0032588 trans-Golgi network membrane | NAS PMID:15377783 Crystal structure of the clathrin adaptor protein 1 core. | ACCEPT | Summary: TGN membrane stated by the AP-1 core structure paper. Reason: The paper opens by identifying AP-1 as the complex that functions in the TGN and then maps the determinants of that localisation, showing it depends on Arf1 and PI-4-P. sigma1A is an intact chain of the core it crystallised. Correct and core. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:15377783 TGN localization of AP-1 depends on the small GTPase, Arf1, and the phosphoinositide, PI-4-P. PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. |
| GO:0032588 trans-Golgi network membrane | NAS PMID:27057418 Role of the epithelial cell-specific clathrin adaptor comple... | ACCEPT | Summary: TGN membrane stated in the AP-1B/cell-polarity review. Reason: Correct: the review names the TGN as one of the two sorting stations at which AP-1-family adaptors act. Redundant with better sources for the same term but not wrong, and sigma1A is in both the AP-1A and AP-1B variants the review distinguishes. Supporting Evidence: PMID:27057418 Sorting takes place at one of 2 major sorting stations in the cells, the trans-Golgi network (TGN) and recycling endosomes (REs). PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2130641 | ACCEPT | Summary: Reactome places the AP-1 coat on the TGN membrane ('Translocation of TGN-lysosome vesicle to lysosome'). Reason: The TGN membrane is AP-1's principal site of action and sigma1A is required for the complex to be there -- in cells lacking all three sigma1 isoforms, wild-type sigma1A restores TGN/endosomal gamma1 staining and the MEDNIK L90P variant does not. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-2213236 | ACCEPT | Summary: Reactome places the AP-1 coat on the TGN membrane ('TGN-lysosome vesicle uncoating and release of nonameric complex to lysosome'). Reason: The TGN membrane is AP-1's principal site of action and sigma1A is required for the complex to be there -- in cells lacking all three sigma1 isoforms, wild-type sigma1A restores TGN/endosomal gamma1 staining and the MEDNIK L90P variant does not. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-5333658 | ACCEPT | Summary: Reactome places the AP-1 coat on the TGN membrane ('CLAT:AP1:CLVS bind PI(3,5)P2'). Reason: The TGN membrane is AP-1's principal site of action and sigma1A is required for the complex to be there -- in cells lacking all three sigma1 isoforms, wild-type sigma1A restores TGN/endosomal gamma1 staining and the MEDNIK L90P variant does not. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-8951498 | ACCEPT | Summary: Reactome places the AP-1 coat on the TGN membrane ('Dissociation of Arf1:GDP, AP-1 Clathrin coated nonameric complex'). Reason: The TGN membrane is AP-1's principal site of action and sigma1A is required for the complex to be there -- in cells lacking all three sigma1 isoforms, wild-type sigma1A restores TGN/endosomal gamma1 staining and the MEDNIK L90P variant does not. Reactome cites this reaction to every participant of the AP-1 coat, so the row is one pathway-level assertion projected across the complex rather than independent evidence about sigma1A: a QuickGO query by this reference returns a handful of gene products, essentially the AP-1 subunits plus clathrin and the reaction's cargo. Accepted as core. Supporting Evidence: PMID:15377783 We report the crystal structure of the core of the AP-1 complex, which functions in the trans-Golgi network (TGN). PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not PMID:23415225 AP-1 is a clathrin adaptor complex that sorts cargo between the trans-Golgi network and endosomes. AP-1 recruitment to these compartments requires Arf1-GTP. |
| GO:0035615 clathrin-cargo adaptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: The only molecular-function row on the gene. Correct in substance: sigma1A supplies half of the dileucine cargo-signal binding site. Reason: Accepted, and better supported than its IEA code suggests -- but the support is for a contribution, not for an activity sigma1A has alone. Dileucine sorting signals do not bind any single AP subunit; they bind the gamma-sigma1 hemicomplex, and the same experiments that establish this show mu1 and beta1 binding weakly or not at all. The evidence is specific to sigma1A rather than inherited from AP-1 generically: sigma1A paired with gamma1, but not with the AP-2 alpha or AP-3 delta subunits, binds the LIMP-II and tyrosinase tails; point substitutions in sigma1A itself (V88D, I103S, A63D) abolish the binding; and in the AP-1 crystal structure that contains this exact protein as chain S, the HIV-1 Vpu dileucine mimic is bound in a hydrophobic pocket on sigma1 itself. Two caveats recorded rather than acted on. First, the term's GO definition says 'responsible for the formation of endocytic vesicles', which does not describe AP-1; the label fits, the definition does not, and that mismatch is raised as a suggested question rather than used to justify a MODIFY, since GO_Central itself applies this term to AP-1 sigma subunits. Second, no GO term exists for the actual activity -- binding a dileucine sorting signal -- which is filed as a proposed new term and an ontology knowledge gap. In core_functions this is expressed as contributes_to_molecular_function, which is the reading the evidence supports. Stated explicitly so it is actionable rather than left implicit in core_functions: the recommendation to GOA and InterPro2GO is that this row's qualifier should be contributes_to rather than enables. ACCEPT is used because the term itself is right and the action vocabulary has no qualifier-change option; the qualifier is the only part that overstates. The precedent is already in GO: pombe vas2 carries GO:0035615 as IC contributes_to with GO:0030121 as the with-field, and human AP2S1 carries it as TAS contributes_to (PMID:12121421) -- the latter read from a live QuickGO annotation query on UniProtKB:P53680, since this repository has no AP2S1 gene directory to check it against. The pattern is sharper than a simple precedent: the vas2 record also carries an InterPro IEA row for this same term with enables, exactly as AP1S1 does here. So the enables/contributes_to split tracks the evidence pipeline rather than the biology, and enables on AP1S1 is what the InterPro2GO route emits by default rather than a considered judgment about this subunit. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044733 Β· InterPro IPR044733, AP-1 complex subunit sigma (family) SUPPORTS TRANSFER GO:0035615 is one of this family entry's three GO mappings per the InterPro API. Because the entry is AP-1-sigma-specific, the mapping does not over-propagate across the wider adaptor-sigma family. Independent experimental evidence on sigma1A itself (hemicomplex binding assays, point mutants, and the sigma1-containing AP-1 structure) supports the same conclusion far more strongly than the signature does, so this row is not carrying the claim on its own. Supporting Evidence: PMID:21097499 signals, on the other hand, do not bind to any single AP subunit but to combinations of Ξ³-Ο1, Ξ±-Ο2, and Ξ΄-Ο3 subunits, as demonstrated by the use of yeast three-hybrid (Y3H) and in vitro binding assays PMID:17360967 the gamma/sigma1 or alpha/sigma2 hemicomplexes bound the dileucine-based motifs of several proteins quite strongly, whereas binding by the beta1/mu1 and beta2/mu2 hemicomplexes, and the individual beta or mu subunits, was extremely weak or undetectable. PMID:39269494 These experiments showed that Ο1AWT, in combination with Ξ³1 but not with the homologous AP-2 Ξ±C and AP-3 Ξ΄ subunits, interacted with the cytosolic tail of LIMP-II and tyrosinase PMID:24843023 E62 forms a salt bridge with R15 of AP1 Ξ³ subunit, fulfilling the role of the βacidic residueβ within the sorting motif, while L66 and V67 embed into the hydrophobic pocket on AP1 Ο1 that accommodates the canonical dileucine residues PMID:21097499 This is evidenced by the loss of signal binding by the Ο2 V88D or L103S substitutions and the homologous Ο1A V88D and I103S and Ο3A V94D and L109S substitutions. |
| GO:0043195 terminal bouton | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Terminal bouton, transferred by Ensembl Compara from mouse Ap1s1 -- the true 1:1 ortholog, not AP1S2. Reason: A presynaptic terminal is a place a ubiquitous coat adaptor can legitimately be found without it being what the protein is for. The donor's evidence is IDA from PMID:20203623, a paper titled for sigma1B. That is a trap, not a defect. The cached record is abstract-only, MGI curators read the full text, and the abstract itself contrasts the two isoforms -- it states that the ubiquitously expressed AP-1-sigma1A complex sorts between the TGN and early endosomes while the sigma1B-deficient mice have the synaptic phenotype -- so the study plainly assays sigma1A as well. Removing this on the grounds that the title names a paralog would be exactly the error of overruling a curator from evidence I cannot see. Graded non-core instead: the localisation is real but neuronal and tissue-restricted, whereas sigma1A is a ubiquitously expressed adaptor subunit whose core business is TGN/endosomal sorting. Brain is nonetheless the tissue of highest sigma1A expression, so the annotation is not incongruous. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P61967 Β· Ap1s1, Mus musculus sigma1A -- the 1:1 ortholog, not the neuronal paralog SUPPORTS TRANSFER Checked rather than assumed: P61967 resolves to AP1S1_MOUSE, gene Ap1s1, Mus musculus, Swiss-Prot. It is the direct ortholog of the target and the same subunit, so this is a clean 1:1 transfer. QuickGO shows the mouse source rows are IDA from PMID:20203623. ensembl:ENSMUSP00000106709 Β· Mouse Ensembl protein backing the Compara ortholog call SUPPORTS TRANSFER The Ensembl protein identifier for the same mouse Ap1s1 gene product; it is the pipeline's handle on the orthology assertion rather than a second, independent donor. Supporting Evidence: PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. PMID:20203623 The expressions of sigma1A and sigma1B are highest in the brain. PMID:27411398 Brain is the tissue with the highest Ο1A and Ο1B expression. |
| GO:0060155 platelet dense granule organization | NAS PMID:23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiqui... | KEEP AS NON CORE | Summary: Platelet dense granule organization, from the Rab32/Rab38 LRO review. Reason: Dense granules are lysosome-related organelles, and AP-1 is one of the three machineries the review places on the LRO biogenesis route alongside AP-3 and BLOC-2, so the claim is not baseless. But it is doubly indirect: the statement is about the AP-1 complex rather than sigma1A, and it is about lysosome-related organelles generally rather than platelet dense granules specifically, which the review discusses mainly through melanosomes. It is also a megaphone reference -- 178 annotations over 48 gene products in QuickGO. A megakaryocyte-restricted process cannot be the core function of a ubiquitously expressed adaptor subunit. Retained as non-core. Supporting Evidence: PMID:23247405 BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. |
| GO:0098793 presynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Presynapse, transferred by Ensembl Compara from mouse Ap1s1's IDA. Real but neuron-specific. Reason: The same transfer as the terminal-bouton row and graded the same way; the two are one piece of evidence, not two. The donor's evidence is IDA from PMID:20203623, a paper titled for sigma1B. That is a trap, not a defect. The cached record is abstract-only, MGI curators read the full text, and the abstract itself contrasts the two isoforms -- it states that the ubiquitously expressed AP-1-sigma1A complex sorts between the TGN and early endosomes while the sigma1B-deficient mice have the synaptic phenotype -- so the study plainly assays sigma1A as well. Removing this on the grounds that the title names a paralog would be exactly the error of overruling a curator from evidence I cannot see. Graded non-core instead: the localisation is real but neuronal and tissue-restricted, whereas sigma1A is a ubiquitously expressed adaptor subunit whose core business is TGN/endosomal sorting. Brain is nonetheless the tissue of highest sigma1A expression, so the annotation is not incongruous. The sigma1A-specific synaptic biology that does exist -- promoting early-endosome maturation through an ArfGAP1/Rabex-5 route -- is mouse synaptosome work and is recorded as a knowledge gap rather than annotated on the human gene. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P61967 Β· Ap1s1, Mus musculus sigma1A -- the 1:1 ortholog, not the neuronal paralog SUPPORTS TRANSFER Checked rather than assumed: P61967 resolves to AP1S1_MOUSE, gene Ap1s1, Mus musculus, Swiss-Prot. It is the direct ortholog of the target and the same subunit, so this is a clean 1:1 transfer. QuickGO shows the mouse source rows are IDA from PMID:20203623. ensembl:ENSMUSP00000106709 Β· Mouse Ensembl protein backing the Compara ortholog call SUPPORTS TRANSFER The Ensembl protein identifier for the same mouse Ap1s1 gene product; it is the pipeline's handle on the orthology assertion rather than a second, independent donor. Supporting Evidence: PMID:20203623 The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. PMID:27411398 AP-1/Ο1A and AP-1/Ο1B regulate maturation of these early endosomes into multivesicular body late endosomes, thereby controlling synaptic vesicle protein transport into a degradative pathway. PMID:20203623 The expressions of sigma1A and sigma1B are highest in the brain. |
| GO:0110010 basolateral protein secretion | NAS PMID:27057418 Role of the epithelial cell-specific clathrin adaptor comple... | KEEP AS NON CORE | Summary: Basolateral protein secretion, from the AP-1B cell-polarity review. Reason: Basolateral sorting is an established AP-1 function and sigma1A participates in it, since the sigma subunit is shared between the ubiquitous AP-1A and the epithelial AP-1B variant -- the variant-defining subunit is mu1B, not sigma1. Relevance to this gene is reinforced by the AP1S1 knockout phenotype in intestinal epithelium, where tight-junction proteins are mislocalised and barrier function fails, and by the enteropathy in MEDNIK. It stays non-core because it is an epithelium-restricted specialisation of the general TGN/endosome sorting activity that the accepted core terms already capture, and because the cited review is about AP-1B rather than about sigma1A. Supporting Evidence: PMID:27057418 AP-1B facilitates basolateral sorting from REs. PMID:39269494 AP-1 is a clathrin-associated complex that mediates sorting of transmembrane proteins between the trans-Golgi network (TGN) and endosomes in all cells, as well as polarized sorting to the basolateral surface of epithelial cells and the somatodendritic domain of neurons PMID:32306098 We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. |
| GO:1903232 melanosome assembly | NAS PMID:23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiqui... | KEEP AS NON CORE | Summary: Melanosome assembly, from the Rab32/Rab38 review. Better grounded than it looks, because tyrosinase is a demonstrated gamma1-sigma1A dileucine cargo. Reason: This row would be a bare complex-level projection except for one connection the review itself supplies and the dileucine literature completes. The review places AP-1 on early/recycling endosome tubules loading tyrosinase and Tyrp1 toward maturing melanosomes; and the cargo signal in the tyrosinase tail is one of the dileucine signals shown to bind the gamma1-sigma1A hemicomplex specifically, with the MEDNIK L90P substitution abolishing that interaction. So there is a real, subunit-level mechanistic link from sigma1A to melanosomal cargo, which is more than can be said for the platelet-granule row. It remains non-core because melanosome biogenesis is melanocyte-restricted while sigma1A is ubiquitous, and because reduced pigmentation is only one facet of the AP1S1 loss-of-function phenotype. Supporting Evidence: PMID:23247405 Two small GTPases, Rab32 and Rab38, are key proteins in the biogenesis of melanosomes and were recently shown to redirect the ubiquitous machinery-BLOC-2, AP-1 and AP-3-to traffic specialized cargoes to melanosomes in melanocytes. PMID:39269494 These experiments showed that Ο1AWT, in combination with Ξ³1 but not with the homologous AP-2 Ξ±C and AP-3 Ξ΄ subunits, interacted with the cytosolic tail of LIMP-II and tyrosinase PMID:39269494 Importantly, we observed that the L90P substitution completely abolished the interaction of the Ξ³1-Ο1A hemicomplex with the LIMP-II and tyrosinase tails in the Y3H assay |
| GO:0005198 structural molecule activity | IMP PMID:39269494 Revising pathogenesis of AP1S1-related MEDNIK syndrome: a mi... | NEW | Summary: Proposed. GOA gives AP1S1 exactly one molecular-function term, and it is a complex-level one inherited from a domain signature. The subunit's own contribution -- holding the AP-1 heterotetramer together, without which the complex neither assembles nor reaches its membranes -- is directly demonstrated in human cells and is annotated nowhere. Reason: GO:0005198 is defined as 'The action of a molecule that contributes to the structural integrity of a complex', which is precisely what this evidence shows, and it is the subunit-level function that the schema asks for alongside a contributes_to complex activity. The demonstration is in human cells and runs in both directions. Positive: myc-tagged wild-type sigma1A co-immunoprecipitates with endogenous gamma1, restores gamma1 protein levels in HAP1 cells knocked out for all three sigma1 isoforms, and rescues gamma1 staining on TGN and endosomal membranes. Negative: the MEDNIK L90P substitution reduces gamma1 co-immunoprecipitation to 0-13% of wild type, fails to restore gamma1 levels, and fails to rescue membrane association -- and the authors attribute the membrane defect to impaired assembly of the whole complex rather than to a separate targeting role. So the structural contribution is not inferred from the protein being small and bound: it is the measured consequence of removing it. Coded IMP rather than IDA because the readouts come from transfected constructs in a knockout background, which is a genetic perturbation and not observation of the native protein. This is a coverage gap rather than an over-annotation -- QuickGO carries no GO:0005198 annotation for human AP1S1 -- and it is kept deliberately generic: the more interesting subunit-level activity, dileucine sorting-signal binding, has no GO term at all and is filed under proposed_new_terms. One apparent tension worth pre-empting: this review argues that sigma1A is not a structural filler, and then the single molecular-function row it adds is 'structural molecule activity'. Both hold at once. The subunit genuinely does hold the complex together -- that is what this row records, and it is the part GO can currently express -- while the cargo-recognition activity that makes it more than a filler has no term to be annotated to. Supporting Evidence: PMID:39269494 The Ο1A L90P variant is largely unable to assemble into the AP-1 complex. PMID:39269494 Reciprocal co-immunoprecipitation experiments showed that assembly of Ξ³1 with Ο1AL90P was reduced to 0β13% relative to Ο1AWT PMID:39269494 Expression of myc-tagged Ο1AWT in these cells resulted in partial restoration of endogenous Ξ³1 levels, whereas expression of myc-tagged Ο1AL90P led to minimal or no recovery relative to untransfected cells PMID:39269494 Expression of myc-tagged Ο1AWT rescued TGN/endosomal Ξ³1 staining, whereas expression of myc-tagged Ο1AL90P did not PMID:39269494 These data indicated that the Ο1A L90P substitution disrupts the association of Ξ³1 with TGN/endosomes, likely due to impaired assembly of the whole AP-1 complex. PMID:15377783 The AP-1 core comprises N-terminal fragments of the two large chains, beta1 and gamma, and the intact medium and small chains, micro1 and sigma1. |
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Download this section (compressed HTML)Q: GO:0035615 clathrin-cargo adaptor activity is defined as 'Bringing together a cargo protein with clathrin, responsible for the formation of endocytic vesicles', yet GO_Central applies it to AP-1 sigma subunits, which act at the TGN and endosomes rather than in endocytosis. Should the definition be broadened to cover non-endocytic clathrin coats, or should AP-1 subunits move to a different term?
Suggested experts: Bonifacino JS, Mattera R
Q: All three sigma1 isoforms bind every dileucine signal tested and all assemble with gamma1. What then confines the MEDNIK phenotype to loss of sigma1A -- is it purely expression level, or do sigma1B and sigma1C fail to substitute for reasons that are not visible in a binding assay?
Suggested experts: Schu P, Bonifacino JS
Q: The AP-4 epsilon-sigma4 hemicomplex does not bind dileucine signals even though sigma4 retains the pocket residues that matter in sigma1A, sigma2 and sigma3A. Where does the specificity actually reside -- in the large subunit, in the surrounding sigma surface, or in whether the pocket is exposed in the AP-4 conformation?
Suggested experts: Mattera R, Bonifacino JS, Hurley JH
Q: Is the ArfGAP1-dependent, coat-independent role of sigma1A in early-endosome maturation a general property of the ubiquitous AP-1/sigma1A complex, or a neuron-specific adaptation seen only in the synaptosome preparations where it was characterised?
Suggested experts: Schu P, Candiello E
Experiment: Build chimeric hemicomplexes in the yeast three-hybrid format already validated for this question: gamma1 paired with sigma4, epsilon paired with sigma1A, and reciprocal swaps of the sigma C-terminal helical region. Score binding against the Nef, tyrosinase and LIMP-II tails, with the wild-type gamma1-sigma1A and epsilon-sigma4 pairs as the positive and negative controls. If specificity tracks the large subunit, gamma1-sigma4 binds; if it tracks the sigma surface outside the pocket, it does not.
Hypothesis: Dileucine-signal binding specificity among AP sigma subunits is conferred by the partner large subunit rather than by the sigma pocket, which is why sigma4 retains the pocket residues but the AP-4 hemicomplex does not bind.
Type: yeast three-hybrid with chimeric subunits
Experiment: Apply the in vitro AP-1 vesicle-formation assay with label-free quantitative mass spectrometry, but comparing wild-type cells against AP1S1-deficient cells rather than the AP1G1-deficient cells used previously, and add a rescue arm expressing the assembly-incompetent L90P variant. Cargo lost in the knockout and restored by wild-type but not L90P sigma1A is sigma-dependent. Cross the resulting list against proteins carrying acidic dileucine motifs compatible with the gamma1-sigma1A preference.
Hypothesis: sigma1A selects a definable cargo set that only partly overlaps the cargo set selected by the gamma1 large subunit, and the MEDNIK phenotype follows from the sigma-dependent subset.
Type: vesicle reconstitution with quantitative proteomics
Experiment: Use the CaCo2 AP1S1-knockout intestinal epithelial model, in which tight-junction mislocalisation, reduced transepithelial resistance and abnormal lumen formation are established and reversible by wild-type AP1S1. Ask whether expressing AP1S2 or AP1S3 at matched levels rescues the same readouts. Full rescue argues the isoforms are interchangeable and the disease is a dosage problem; failure to rescue points to an isoform-specific property that binding assays have not captured.
Hypothesis: sigma1B and sigma1C can functionally replace sigma1A when expressed in the tissues affected in MEDNIK, so the disease reflects expression rather than an intrinsic isoform difference.
Type: paralog complementation in a knockout epithelial model
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: What distinguishes the sigma subunits that bind dileucine signals from the one that does not is unidentified. The AP-4 epsilon-sigma4 hemicomplex demonstrably fails to bind these signals, yet sigma4 retains the same pocket residues as the binders, so the specificity determinant is not the pocket itself.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: The binding/non-binding phenotypes are firmly established by yeast three-hybrid across AP-1, AP-2, AP-3 and AP-4 hemicomplexes, and the pocket residues are known from the AP-2 structure and confirmed by mutagenesis in sigma1A, sigma2 and sigma3A. The bioinformatics analysis in this review maps that pocket onto all six human sigma paralogs and finds sigma4 scoring 4/5 identical, the same as sigma1A, sigma1B and sigma1C.
Significance: It means residue conservation at this site cannot be used to predict dileucine binding in an uncharacterised sigma subunit or in a non-model organism, which is exactly the inference an automated pipeline would make. The determinant most likely lies in the partner large subunit or in conformational accessibility of the pocket, but that has not been tested.
What would resolve it: Swap the surrounding surface between sigma1A and sigma4, or test chimeric hemicomplexes pairing gamma1 with sigma4 and epsilon with sigma1A, and ask which component confers binding.
Provenance (the field's own admissions):
Gap: Why loss of sigma1A specifically produces the MEDNIK organ spectrum -- skin, intestine, ear, peripheral nerve, brain and copper handling -- is unknown. The cellular basis for the division of labour between the three sigma1 isoforms has not been established, so it is not known whether the phenotype reflects sigma1A's ubiquitous expression, a cargo preference unique to it, or the absence of compensation by sigma1B and sigma1C in those tissues.
OPEN BIOLOGY BP_DARK
What is known: The biochemistry gives no isoform difference to work with: all three sigma1 isoforms recognise every dileucine signal tested, and all three assemble with gamma1. Expression differs -- sigma1A is ubiquitous while sigma1B and sigma1C are restricted -- and the disease alleles are well characterised as loss of function.
Significance: This is what stands between a molecular mechanism and an explanation of the disease, and it determines whether raising sigma1B or sigma1C expression could be therapeutic.
What would resolve it: Tissue-resolved comparison of AP-1 cargo repertoires in sigma1A-null versus sigma1B-null and sigma1C-null cells, and a test of whether sigma1B or sigma1C overexpression rescues the sigma1A-null epithelial barrier phenotype.
Provenance (the field's own admissions):
Gap: The cargo repertoire that sigma1A selects is not systematically mapped. Individual cargoes are known -- ATP7A and ATP7B, LIMP-II, tyrosinase, EGFR, tight-junction proteins -- but they were found one at a time, and no unbiased survey has asked which of them depend on the sigma subunit as opposed to the complex.
NARROWING BIOLOGYCURATION BP_DARK
What is known: The recognition mechanism is solved and a handful of cargoes are validated individually, including two whose tails were tested directly against the gamma1-sigma1A hemicomplex. Recent AP-1 vesicle proteomics exists but perturbs the gamma1 large subunit rather than sigma1A.
Significance: Without the repertoire it is not possible to say which parts of the MEDNIK phenotype follow from which mis-sorted protein, and GO cannot record has_input relationships for an activity whose substrates are only anecdotally known.
What would resolve it: Apply the existing AP-1 vesicle-proteomics assay to sigma1A-deficient cells rather than gamma1-deficient cells, and cross the hits against proteins carrying gamma1-sigma1A-compatible dileucine motifs.
Provenance (the field's own admissions):
Gap: Whether the coat-independent role reported for sigma1A -- promoting early-endosome maturation by raising endosomal Rabex-5 and Vps34 activity through ArfGAP1 -- operates in human cells, and whether it is separable from the complex's sorting function, has not been tested.
OPEN BIOLOGYCURATION MF_DARK
What is known: The mechanism was worked out in mouse synaptosomes and rests on an indirect link: Rabex-5 binds sigma1B and not sigma1A directly, with ArfGAP1 proposed as the connector. It is explicitly presented as a mode of action that does not involve AP-1 coated-vesicle formation.
Significance: If real in human cells it would be a second, structurally distinct molecular function for the same subunit, which no current annotation captures; it is the reason no NEW human annotation was created for endosome maturation in this review.
What would resolve it: Reproduce the ArfGAP1-dependent Rabex-5 recruitment in human cells using the triple-sigma1-knockout background already available, comparing sigma1A rescue with an assembly-incompetent variant such as L90P to separate coat-dependent from coat-independent effects.
Provenance (the field's own admissions):
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