CBLIF

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation placing CBLIF in the extracellular region. CBLIF is a secreted protein that acts extracellularly (in the gut lumen / on the intestinal apical surface) to bind and deliver cobalamin, so this is correct and part of the core biology. Reason: UniProt records the protein as secreted, and it functions extracellularly as a cobalamin carrier. The IBA call is consistent with experimental localization and the known biology. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0015889 cobalamin transport	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to cobalamin transport. CBLIF is required for intestinal absorption of dietary cobalamin, binding it and mediating cubam(CUBN/AMN)-dependent uptake in the ileum. This is a core biological process for the gene. Reason: Supported experimentally by human loss-of-function disease (hereditary IF deficiency) and by the well-established IF-cobalamin/cubam absorption pathway. Correct and core. Supporting Evidence: PMID:20237569 This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless. file:human/CBLIF/CBLIF-uniprot.txt Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.
GO:0031419 cobalamin binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to cobalamin binding, the defining molecular function of CBLIF. This is directly supported by the crystal structure of the human IF-cobalamin complex and by defined cobalamin-contacting residues in UniProt. Reason: Cobalamin binding is the core molecular function of intrinsic factor, confirmed by structural and biochemical evidence. The IBA call is at the correct level of specificity. Supporting Evidence: PMID:17954916 the Cbl is bound at the interface of the domains in a base-on conformation
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation to extracellular region derived from the UniProt "Secreted" subcellular location keyword mapping. Consistent with the experimental and phylogenetic evidence for a secreted protein. Reason: Redundant with the IBA/IDA extracellular-region calls but correct; the SubCell mapping accurately reflects the secreted nature of the protein. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0015889 cobalamin transport	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation (IPR002157, cobalamin-binding protein) to cobalamin transport. Consistent with the experimentally supported transport role. Reason: The InterPro family mapping is biologically appropriate for CBLIF and matches the experimental IMP/IBA/TAS annotations to the same process. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum.
GO:0031419 cobalamin binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation (IPR002157) to cobalamin binding. Matches the structurally validated core molecular function. Reason: The cobalamin-binding domain assignment is correct for CBLIF and the mapped MF term is the defining function, corroborated by crystallography (PMID:17954916). Supporting Evidence: PMID:17954916 The structure of intrinsic factor (IF) in complex with cobalamin (Cbl) was determined at 2.6-A resolution.
GO:0005515 protein binding	IPI PMID:20237569 Structural basis for receptor recognition of vitamin-B(12)-i...	MARK AS OVER ANNOTATED	Summary: IPI annotation to the generic term protein binding, capturing the interaction with cubilin (CUBN, IntAct O60494). This interaction is real and functionally central (the IF-Cbl complex is recognized by the CUBN/AMN cubam receptor for ileal uptake), and is structurally defined. However, the bare "protein binding" term is uninformative about the actual function. Reason: Per curation guidance, the uninformative "protein binding" term should not be treated as a core function even though the underlying CUBN interaction is genuine. The functional content of this interaction is better represented by the cobalamin-transport process and the cargo receptor ligand activity annotations, and by the specific CUBN partner recorded in UniProt SUBUNIT. Supporting Evidence: PMID:20237569 how two distant CUB domains embrace the Cbl molecule by binding the two IF domains in a Ca(2+)-dependent manner file:human/CBLIF/CBLIF-uniprot.txt Interacts with CUBN (via CUB domains).
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI annotation to protein binding from the HuRI high-throughput binary (yeast two-hybrid) interactome screen. The recorded partners (FFAR2, SLC13A4, SLC22A23, SLC7A1, SLC7A14, TMEM237) are membrane transporters/GPCRs with no established biological relationship to a secreted cobalamin-binding protein. Reason: These are uninformative large-scale screen hits and the bare "protein binding" term conveys no functional information; they are very unlikely to reflect physiological partners of a secreted extracellular Cbl carrier. Marked as over-annotated rather than removed, per policy for IPI protein-binding annotations. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions
GO:0015889 cobalamin transport	TAS Reactome:R-HSA-9758881	ACCEPT	Summary: Reactome TAS annotation to cobalamin transport, from the "Uptake of dietary cobalamins into enterocytes" pathway. CBLIF binds dietary cobalamin and delivers it to the ileal cubam receptor for absorption; this is the core process. Reason: Reactome's pathway representation accurately captures CBLIF's role in the intestinal cobalamin absorption pathway, consistent with experimental (IMP) and phylogenetic (IBA) annotations. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum.
GO:0140355 cargo receptor ligand activity	EXP PMID:17954916 Crystal structure of human intrinsic factor: cobalamin compl...	ACCEPT	Summary: Experimental annotation to cargo receptor ligand activity. The cobalamin-loaded CBLIF complex is the ligand recognized by the cubam (CUBN/AMN) cargo receptor, which then internalizes it by endocytosis in the ileum. This captures the receptor-recognition facet of CBLIF's transport function. Reason: Structural work shows CUBN recognizes the Cbl-saturated IF complex, and the complex is taken up by receptor-mediated endocytosis; "cargo receptor ligand activity" is the appropriate MF for a secreted carrier ligand that engages an endocytic receptor. This is an informative, core molecular function. Supporting Evidence: PMID:17954916 CUB recognizes both the full-length Cbl-saturated IF complex and the Cbl-saturated cleaved IF complex but not the isolated file:human/CBLIF/CBLIF-uniprot.txt After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3000103	ACCEPT	Summary: Reactome TAS localization to extracellular region for the reaction in which the cubam (CUBN:AMN) receptor binds the secreted CBLIF:RCbl complex. Correct for a secreted protein acting on the intestinal luminal/apical surface. Reason: Consistent with the secreted subcellular location and with the other extracellular annotations. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3000120	ACCEPT	Summary: Reactome TAS localization to extracellular region for the reaction "CBLIF binds RCbl" (binding of free cobalamin by secreted intrinsic factor in the intestinal lumen). Correct for the secreted protein. Reason: Redundant with other extracellular-region calls but accurate; the binding of cobalamin by CBLIF occurs extracellularly in the gut lumen. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3000137	ACCEPT	Summary: Reactome TAS localization to extracellular region for the cubam-mediated uptake reaction. Correct for the secreted CBLIF:RCbl complex engaging the cell-surface receptor prior to internalization. Reason: Consistent with the secreted nature of the protein and its extracellular site of action. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3296462	ACCEPT	Summary: Reactome TAS localization to extracellular region for the disease reaction "Defective CUBN does not transport GIF:Cbl". The extracellular localization of CBLIF is correct regardless of the disease context. Reason: Accurate secreted localization; redundant with the other extracellular annotations. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3296477	ACCEPT	Summary: Reactome TAS localization to extracellular region for the disease reaction "Defective AMN does not transport GIF:Cbl". The secreted CBLIF localization is correct. Reason: Accurate secreted localization; redundant with the other extracellular annotations. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3315455	ACCEPT	Summary: Reactome TAS localization to extracellular region for the disease reaction "Defective CBLIF does not bind Cbl". The secreted CBLIF localization is correct. Reason: Accurate secreted localization; redundant with the other extracellular annotations. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt SUBCELLULAR LOCATION: Secreted.
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-3000137	KEEP AS NON CORE	Summary: Reactome TAS localization to lysosomal lumen. After cubam-mediated endocytosis in the ileal enterocyte, the CBLIF:RCbl complex is delivered to lysosomes, where cobalamin is released and CBLIF is degraded. This is a genuine trafficking endpoint but not the protein's core (secreted, cobalamin-binding) function. Reason: The lysosomal-lumen localization reflects the fate of the internalized complex in the target enterocyte rather than where CBLIF performs its defining function; retain as a correct but non-core localization. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-3000243	KEEP AS NON CORE	Summary: Reactome TAS localization to lysosomal lumen for the reaction in which a lysosomal protease degrades CBLIF:RCbl to release cobalamin. Same non-core trafficking endpoint as R-HSA-3000137. Reason: Correct localization of the internalized complex within the enterocyte lysosome, but peripheral to CBLIF's defining secreted cobalamin-binding function. Supporting Evidence: file:human/CBLIF/CBLIF-uniprot.txt After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.
GO:0005576 extracellular region	IDA PMID:14695536 A genetic polymorphism in the coding region of the gastric i...	ACCEPT	Summary: IDA localization to extracellular region. Recombinant CBLIF expressed in COS-7 cells was secreted with size, secretion rate, and pepsin sensitivity similar to native IF, supporting the secreted/extracellular localization. Reason: Direct experimental support for secretion of the protein; core extracellular localization. Supporting Evidence: PMID:14695536 The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF.
GO:0005768 endosome	IDA PMID:8886952 Human gastric intrinsic factor expression is not restricted ...	KEEP AS NON CORE	Summary: IDA localization to endosome, from immunoelectron microscopy of human gastric mucosa showing highest intrinsic factor antigen density on endocytic (and apical) membranes of parietal cells. Reflects the intracellular biosynthetic/secretory and endocytic compartments in the producing cell rather than the core secreted function. Reason: A real, experimentally observed localization within intrinsic-factor-producing cells, but peripheral to the protein's defining extracellular cobalamin-binding/transport role. Supporting Evidence: PMID:8886952 Immunoelectron microscopy demonstrated the highest antigen density on endocytic and apical membranes of parietal cells.
GO:0005902 microvillus	IDA PMID:8886952 Human gastric intrinsic factor expression is not restricted ...	KEEP AS NON CORE	Summary: IDA localization to microvillus, from the same immuno-localization study of intrinsic factor in gastric mucosa. Represents cell-surface/apical membrane localization in the producing parietal cell; non-core relative to the secreted function. Reason: Experimentally observed apical/microvillar membrane association in parietal cells; correct but peripheral to CBLIF's core secreted cobalamin-binding/transport function. Supporting Evidence: PMID:8886952 Immunoelectron microscopy demonstrated the highest antigen density on endocytic and apical membranes of parietal cells.
GO:0015889 cobalamin transport	IMP PMID:15738392 Hereditary juvenile cobalamin deficiency caused by mutations...	ACCEPT	Summary: IMP annotation to cobalamin transport based on human genetics: biallelic nonsense and missense GIF (CBLIF) mutations cause hereditary intrinsic factor deficiency with juvenile megaloblastic anemia due to intestinal cobalamin malabsorption. This is the strongest experimental support for CBLIF's role in cobalamin transport/absorption. Reason: Loss-of-function mutations abolishing intestinal cobalamin absorption directly demonstrate CBLIF's requirement for cobalamin transport; core process. Supporting Evidence: PMID:15738392 harbored homozygous nonsense and missense mutations in these four families and in three additional families. The disease in these cases therefore should be classified as hereditary IF deficiency.
GO:0016324 apical plasma membrane	IDA PMID:8886952 Human gastric intrinsic factor expression is not restricted ...	KEEP AS NON CORE	Summary: IDA localization to apical plasma membrane, from immunoelectron microscopy showing highest intrinsic factor antigen density on apical (and endocytic) membranes of gastric parietal cells. Reflects the apical secretory surface of the producing cell. Reason: Experimentally supported apical membrane association in parietal cells; a correct but non-core localization relative to the secreted extracellular function. Supporting Evidence: PMID:8886952 Immunoelectron microscopy demonstrated the highest antigen density on endocytic and apical membranes of parietal cells.
GO:0031419 cobalamin binding	IDA PMID:14695536 A genetic polymorphism in the coding region of the gastric i...	ACCEPT	Summary: IDA annotation to cobalamin binding, the defining molecular function of CBLIF, assessed for recombinant IF (studied in the context of the congenital IF deficiency-associated Q23R variant). Directly corroborated by the crystal structure of the IF-cobalamin complex. Reason: Cobalamin binding is CBLIF's core molecular function, supported here by direct assay of the recombinant protein and by structural evidence (PMID:17954916). Supporting Evidence: PMID:14695536 The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. PMID:17954916 the Cbl is bound at the interface of the domains in a base-on conformation

Gene Description

Existing Annotations Review

Core Functions

Binds dietary cobalamin (vitamin B12) as a secreted carrier and functions as the ligand recognized by the ileal cubam (CUBN/AMN) cargo receptor, thereby mediating receptor-dependent intestinal absorption of cobalamin.

Acts as the cargo ligand for the ileal endocytic cubam receptor: the cobalamin-loaded CBLIF complex is recognized by CUBN/AMN and internalized by receptor-mediated endocytosis, coupling cobalamin binding to its cellular uptake.

References

📚 Additional Documentation

Notes

📄 View Raw YAML