A1BG (alpha-1B-glycoprotein) is a secreted, glycosylated plasma protein with five immunoglobulin-like domains. It forms a high-affinity, noncovalent complex with CRISP3 in human plasma. Recombinant human A1BG binds CRISP2 and inhibits its sterol binding; coexpression also reduces CAP-protein-dependent sterol export in a yeast reconstruction. The CRISP2 interaction involves A1BG immunoglobulin domain 3 and depends on magnesium. A1BG itself does not bind cholesterol sulfate in the reported assay, and its inhibition of CRISP2 sterol binding does not abolish CRISP2 fatty-acid binding. Mouse A1BG associates with cardiomyocyte surfaces, and cardiomyocyte deletion causes female-specific cardiac defects. In an osteosarcoma model, A1BG associates with NAMPT and promotes its protein stability, linking it to NAD metabolism and treatment resistance in that context. The physiological extent of these activities in healthy human tissues remains to be established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: Refine the corroborated peripheral membrane location to the external side of the plasma membrane. Reason: The actual P04217 leaf PTN002482657 descends from membrane IBD PTN002621170 in PTHR11738. This is a PAINT ancestral assertion, not merely transfer from whichever receptor donors were listed. Ortholog surface localization removes the prior supposed architectural contradiction. Retain the source is_active_in qualifier and IBA evidence; the mouse experiment is corroboration, not a human IDA assay. Circulating extracellular protein remains the best established core location. The completed OpenScientist report misses Fig. 4D and incorrectly treats the hydropathy result as excluding every membrane pool. Its own limitations acknowledge peripheral association. The independently reproduced calculation addresses a conventional helix only, so its categorical REMOVE/NOT lead is not adopted. The mouse observation specifically supports the external membrane surface rather than an integral membrane pool; use that more informative location as the replacement without claiming that the broader inherited location was biologically false. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002621170 SUPPORTS TRANSFER Actual ancestor of target PTN002482657 carrying the positive plasma-membrane IBD. Secreted architecture does not establish loss of peripheral membrane association. UniProtKB:Q8NHL6 SUPPORTS TRANSFER Experimental receptor localization contributes to the ancestral inference; evidence is assessed through node placement, not a donor count. UniProtKB:P43626 SUPPORTS TRANSFER Membrane-receptor descendant evidence is consistent with the asserted ancestral location. Proposed replacements: external side of plasma membrane Supporting Evidence: PMID:40270023 A1BG is associated with the outer surface of atrial CMs. file:human/A1BG/A1BG-bioinformatics/RESULTS.md It does not test surface binding, peripheral association, receptor-complex function |
| GO:0004888 transmembrane signaling receptor activity | IBA GO_REF:0000033 | UNDECIDED | Summary: Unresolved receptor-capacity inference at an actual ancestor of A1BG. The mature secreted Ig-domain protein has no annotated transmembrane segment or cytoplasmic signaling tail, a relevant divergence from many family receptors. Nevertheless, secretion alone cannot exclude a membrane-associated signaling role, and mouse A1BG surface association is experimentally observed. Reason: P04217 descends from receptor IBD PTN002621170. GO:0004888 describes ligand-dependent transmission of a signal across a membrane; its definition does not say that every component must independently span the membrane. The completed OpenScientist report and independently reproduced hydropathy calculation support absence of a conventional membrane-spanning helix, a relevant mechanistic divergence, but do not demonstrate loss of every receptor-complex role. The report admits that it inferred topology from family membership rather than tracing the target and overlooks the ortholog surface experiment. Neither peripheral association nor cellular NAMPT stabilization demonstrates receptor activity. Retain UNDECIDED without asserting NOT or replacing an unresolved ancestral capacity by a different supported activity. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002621170 UNRESOLVED Verified ancestor carrying the positive receptor IBD. The completed report supplies no independently traced loss or functional exclusion of a receptor-complex role; no canonical transmembrane helix is a relevant mechanistic limitation, not a complete negative assay. UniProtKB:P24071 SUPPORTS TRANSFER FCAR receptor activity grounds the family assertion; does not by itself resolve retention in A1BG. UniProtKB:Q8N423 SUPPORTS TRANSFER LILRB2 receptor evidence contributes to ancestral placement. UniProtKB:Q99706 SUPPORTS TRANSFER KIR2DL4 receptor evidence contributes to ancestral placement. Supporting Evidence: PMID:40270023 A1BG is associated with the outer surface of atrial CMs. PMID:40560034 Co‐IP followed by western blot analysis confirmed a robust interaction between A1BG and NAMPT file:human/A1BG/A1BG-bioinformatics/RESULTS.md This corroborates absence of an ordinary hydrophobic transmembrane helix in canonical mature A1BG. file:human/A1BG/A1BG-report-assessment.md Lack of a canonical helix is a relevant divergence from intrinsic transmembrane receptors, but does not itself demonstrate loss of every enabling receptor-complex role. |
| GO:0060396 growth hormone receptor signaling pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: Unresolved participation in growth-hormone receptor signaling. The source is a genuine mouse A1bg experimental annotation, inherited through verified A1BG ancestor PTN000200788. The accessible abstract of PMID:16723264 establishes GH-dependent hepatic transcript expression, which by itself does not show the protein doing signaling work. Reason: The completed OpenScientist report correctly distinguishes GH-dependent transcript expression from work by the protein in signaling. It claims full-paper access, but supplies only abstract-derived passages and no independently checkable full-text or additional-assay provenance; the source remains abstract-only on independent retrieval. This leaves the concrete source-scope question unresolved and does not establish SOURCE_BAD. Actual target descent from the A1BG-specific PTN000200788 and the mouse A1bg IMP are verified; this is not simply LILR/KIR pairwise transfer. Retain UNDECIDED pending full-primary-text or curator assessment, without a duplicate provider request or a NEW response term based on expression alone. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:2152878 UNRESOLVED Mouse A1bg IMP PMID:16723264. The report recognizes expression dependence, but its assertion of complete-paper access is not independently verifiable from the provided artifacts. Exact functional assay scope remains unresolved; no established source error. PANTHER:PTN000200788 UNRESOLVED Verified A1BG ancestral node above P04217 leaf PTN002482657. A single experimentally grounded descendant can support valid node placement; donor count is not a failure. Supporting Evidence: PMID:16723264 continuous pattern of GH secretion file:human/A1BG/A1BG-report-assessment.md The GH source is mouse A1bg, not an unrelated LILR/KIR donor. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Automatic mapping from the UniProt "Secreted" subcellular-location term. This is the correct core localisation for A1BG, a constitutively secreted plasma glycoprotein purified directly from human plasma. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0005576 extracellular region | HDA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... | ACCEPT | Summary: Retain the experimentally curated extracellular localization from the cited proteomics dataset. It agrees with direct human plasma purification and the secreted mature protein. Target peptide identification in supplementary data was not independently re-counted; the curator assignment is not overruled from an abstract. Supporting Evidence: PMID:27559042 We used proteomics to profile glycoproteins in the human cardiac extracellular matrix (ECM). file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: Retain the experimentally curated extracellular localization from the cited proteomics dataset. It agrees with direct human plasma purification and the secreted mature protein. Target peptide identification in supplementary data was not independently re-counted; the curator assignment is not overruled from an abstract. Supporting Evidence: PMID:27068509 normal and varicose veins were evaluated using proteomics approaches targeting file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: Reactome places A1BG in the secretory-granule lumen and its exocytosis reaction. Retain this curated contextual location; CRISP3 localization is not independent evidence for A1BG localization. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt Reactome; R-HSA-6798695; Neutrophil degranulation. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Reactome places A1BG in ficolin-1-rich granules and their exocytosis reaction. Retain the contextual granule location. Ficolin-rich granules are distinguished from specific granules in the cached reaction summary; no CRISP3-based localization inference is needed. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt Reactome; R-HSA-6798695; Neutrophil degranulation. |
| GO:0031093 platelet alpha granule lumen | TAS Reactome:R-HSA-481007 | KEEP AS NON CORE | Summary: Retain the Reactome-curated platelet alpha-granule lumen location as a contextual site of A1BG storage/release. The reaction does not establish that A1BG performs the exocytosis machinery function. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt Reactome; R-HSA-114608; Platelet degranulation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481007 | ACCEPT | Summary: Reactome places the released A1BG in the extracellular region following platelet alpha-granule exocytosis. Correct core localisation for a secreted plasma glycoprotein. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | ACCEPT | Summary: Reactome secretory-granule exocytosis reaction placing A1BG in the extracellular region. Correct core localisation. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | ACCEPT | Summary: Reactome ficolin-rich granule exocytosis reaction placing A1BG in the extracellular region. Correct core localisation. Supporting Evidence: file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Retain this experimentally curated proteomics localization as a contextual A1BG pool. The source establishes the reported vesicle or microparticle association; this review does not infer contamination, exclusive vesicle targeting, or a vesicle biogenesis activity. Supporting Evidence: PMID:23533145 characterized by a shotgun proteomics procedure. In pooled EPS-urine exosome file:human/A1BG/A1BG-uniprot.txt GO:0070062; C:extracellular exosome; HDA:UniProtKB. |
| GO:0005576 extracellular region | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | ACCEPT | Summary: Retain the experimentally curated extracellular localization from the cited proteomics dataset. It agrees with direct human plasma purification and the secreted mature protein. Target peptide identification in supplementary data was not independently re-counted; the curator assignment is not overruled from an abstract. Supporting Evidence: PMID:16502470 One hundred and fifty-one proteins were identified, 83 of which have not been previously reported in human colostrum, or milk. file:human/A1BG/A1BG-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | KEEP AS NON CORE | Summary: Retain this experimentally curated proteomics localization as a contextual A1BG pool. The source establishes the reported vesicle or microparticle association; this review does not infer contamination, exclusive vesicle targeting, or a vesicle biogenesis activity. Supporting Evidence: PMID:22516433 we have purified microvesicles smaller than 220nm from plasma of healthy donors and performed proteomic, ultra-structural, biochemical and functional analyses. file:human/A1BG/A1BG-uniprot.txt GO:0072562; C:blood microparticle; HDA:UniProtKB. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Retain this experimentally curated proteomics localization as a contextual A1BG pool. The source establishes the reported vesicle or microparticle association; this review does not infer contamination, exclusive vesicle targeting, or a vesicle biogenesis activity. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. file:human/A1BG/A1BG-uniprot.txt GO:0070062; C:extracellular exosome; HDA:UniProtKB. |
| GO:0005576 extracellular region | IDA PMID:3458201 Amino acid sequence of human plasma alpha 1B-glycoprotein: h... | ACCEPT | Summary: The strongest localisation evidence: A1BG was purified from human plasma and its complete amino acid sequence determined by direct protein sequencing, establishing it as a bona fide circulating extracellular protein. This is the core cellular component annotation for the gene. Supporting Evidence: PMID:3458201 The complete amino acid sequence has been determined for alpha 1B-glycoprotein (alpha 1B), a protein of unknown function present in human plasma. |
| GO:0140311 protein sequestering activity | IDA PMID:39433128 Alpha-1-B glycoprotein (A1BG) inhibits sterol-binding and ex... | NEW | Summary: Retain the existing proposed protein-sequestering molecular activity: recombinant human A1BG binds CRISP2, preventing its cholesterol-sulfate binding, and coexpression reduces CAP-dependent yeast sterol export. Ig-domain-3 assays support the interaction surface. CRISP2 palmitate binding and fatty-acid export remain intact; this is selective inhibition, not abolition of all CRISP activity. Reason: Direct binding-dependent inhibition of a partner's ligand interaction fits GO:0140311. The Results quantify greater than 50% inhibition of sterol export; use this assay-level scope instead of treating the abstract's abolished phrasing as complete inhibition. CRISP3 plasma complex formation is corroborating interaction evidence, not by itself proof of CRISP3 inhibition in humans. This MF proposal is supported independently of the unsettled receptor IBA; no sterol-binding or sterol-metabolism process is asserted for A1BG itself. Supporting Evidence: PMID:39433128 this binding is blocked in the presence of A1BG, which by itself does not bind cholesterol sulfate |
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Download this section (compressed HTML)Q: Which CRISP activities are restrained by endogenous A1BG in healthy human plasma, and does CRISP3 binding primarily inhibit activity or form a transport/reservoir complex?
Q: Does membrane-associated A1BG transmit a ligand-dependent signal through a receptor complex, or does it provide another surface-associated function? Mouse atrial cardiomyocyte surface staining in PMID:40270023 establishes that secretion is compatible with a membrane pool.
Q: Does the complete experimental record behind mouse A1bg GO:0060396 establish work by the protein in GH receptor signaling, beyond GH-dependent transcript expression? The completed report supplies no independently verifiable full-text assay provenance; obtain the original full paper or curator assessment rather than another duplicate literature synthesis.
Q: How does A1BG association alter NAMPT lysosomal turnover in osteosarcoma cells, and is this mechanism used outside that cancer setting? Co-immunoprecipitation and colocalization do not alone prove purified binary binding.
Q: Which membrane partners explain the sex-dependent cardiac requirement for mouse A1BG, and are equivalent surface pools present in human cardiomyocytes?
Experiment: Surface plasmon resonance and isothermal titration calorimetry with purified human A1BG against a panel of human CAP-superfamily proteins (CRISP1, CRISP2, CRISP3, GLIPR1, GAPR1), with and without Mg2+, and with an Ig-domain-3 deletion/point-mutant series, to define the sequestering specificity in a purely human system.
Hypothesis: A1BG is a general extracellular sequestering factor for CAP-superfamily proteins, with magnesium-dependent specificity determined by Ig domain 3.
Type: binding assay
Experiment: Structure determination by cryo-EM or crystallography of the A1BG Ig-domain-3/CRISP2 complex, to establish how the Ig domain engages the CAP domain relative to its sterol-binding cavity and its conserved Mg2+-coordinating tetrad.
Hypothesis: A1BG blocks CAP-protein function by occluding the sterol-binding cavity of the CAP domain.
Type: structural biology
Experiment: Assay plasma from A1bg-null mice (and, if available, from humans with A1BG loss-of-function variants) for free versus A1BG-complexed CRISP3 by size-exclusion chromatography and immunoprecipitation, and test CRISP-dependent sterol transfer activity in the two fractions.
Hypothesis: Loss of A1BG releases functionally active CRISP into the circulation.
Type: genetic and biochemical
Experiment: Immunoprecipitate endogenous A1BG from human plasma and quantify co-purifying proteins by label-free or isotope-labelled mass spectrometry, to determine whether CRISP proteins dominate stoichiometrically or whether NAMPT and other reported partners are also present at meaningful levels.
Hypothesis: CRISP proteins are the dominant physiological ligands of circulating A1BG.
Type: interaction proteomics
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