id: P20061
gene_symbol: TCN1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TCN1 encodes transcobalamin-1, also known as haptocorrin (HC), transcobalamin I,
  or protein R / R-binder. It is a secreted, heavily N-glycosylated (~30% carbohydrate)
  cobalamin (vitamin B12)-binding glycoprotein of the eukaryotic cobalamin transport
  protein family (which also includes transcobalamin/TCN2 and gastric intrinsic
  factor/GIF). Haptocorrin is produced by the salivary glands in response to food and
  is a major protein of the specific (secondary) granules of neutrophils; it is present
  in saliva, gastric juice, plasma, bile and other secretions. It binds cobalamin with
  femtomolar affinity and, unlike its paralogues, has broad corrinoid specificity,
  binding cobalamin as well as biologically inactive cobalamin analogues (corrinoids).
  Functionally it protects dietary B12 from the acidic environment of the stomach and
  carries the majority of circulating plasma B12, and it scavenges corrinoid analogues
  for hepatobiliary clearance. It is not the carrier that delivers B12 into cells (that
  role belongs to transcobalamin/TCN2 acting through the CD320 receptor, which does not
  recognize haptocorrin). TCN1 is not an enzyme; its core molecular function is cobalamin
  binding. Elevated serum haptocorrin is observed as a tumour marker in some cancers.
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that TCN1 acts in the extracellular region.
      Correct: haptocorrin is a secreted protein acting in saliva, gastric juice,
      plasma and other extracellular fluids, so extracellular region is an appropriate
      and core localization. GO:0005576 is the exact extracellular CC term also carried
      elsewhere in the GOA.
    action: ACCEPT
    reason: >-
      TCN1 is a secreted cobalamin-binding glycoprotein; extracellular region is the
      correct cellular component and is corroborated by the UniProt "Secreted"
      subcellular location, proteomic detection in plasma/saliva/colostrum, and Reactome.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that TCN1 is involved in cobalamin transport. This
      is the correct core biological process: haptocorrin binds dietary/plasma cobalamin
      (and corrinoid analogues) and participates in B12 transport, protecting acid-labile
      cobalamin in the stomach and carrying most plasma B12.
    action: ACCEPT
    reason: >-
      Cobalamin transport is the established core biological process of the cobalamin
      transport protein family; TCN1 binds and carries cobalamin in secretions and plasma.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Binds vitamin B12 with femtomolar affinity and protects it"
    - reference_id: PMID:23846701
      supporting_text: >-
        a similar overall structure but a different selectivity for corrinoids.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) inference of cobalamin binding. This is the core molecular
      function of TCN1/haptocorrin, directly demonstrated by the crystal structures of
      human HC bound to cyanocobalamin and cobinamide and by defined cobalamin-binding
      residues in UniProt. GO:0031419 is the exact current MF term in the GOA.
    action: ACCEPT
    reason: >-
      Cobalamin binding is directly established experimentally (X-ray structures,
      defined binding site, femtomolar affinity) and is the central molecular function
      of the protein.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Binds vitamin B12 with femtomolar affinity and protects it"
    - reference_id: PMID:23846701
      supporting_text: >-
        a similar overall structure but a different selectivity for corrinoids.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic mapping from the UniProt Swiss-Prot subcellular location ("Secreted")
      to extracellular region. Consistent with the curated secreted localization; correct.
    action: ACCEPT
    reason: >-
      The SubCell "Secreted" -> extracellular region mapping is accurate for this
      secreted glycoprotein and agrees with the IBA, HDA and Reactome CC annotations.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO mapping (IPR002157, cobalamin-binding protein) to cobalamin transport.
      TCN1 belongs to this family and does participate in cobalamin transport, so the
      mapping is appropriate.
    action: ACCEPT
    reason: >-
      The cobalamin-binding-protein InterPro signature correctly maps to the family's
      cobalamin transport process, consistent with the experimental and IBA evidence.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Belongs to the eukaryotic cobalamin transport proteins"
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO mapping (IPR002157) to cobalamin binding. Correct and specific:
      the signature captures the cobalamin-binding fold and TCN1 is experimentally shown
      to bind cobalamin.
    action: ACCEPT
    reason: >-
      InterPro cobalamin-binding-protein signature maps precisely to the demonstrated
      core molecular function.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Belongs to the eukaryotic cobalamin transport proteins"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      IPI annotation to the uninformative "protein binding" term, supported by a single
      high-throughput yeast two-hybrid interaction with junctophilin-3 (JPH3, Q8WXH2)
      from a neurodegenerative-disease interactome screen. The interaction is recorded in
      UniProt/IntAct but has no functional follow-up and does not describe an informative
      molecular function for this secreted cobalamin-binding protein. There is no
      established biology linking secreted haptocorrin to the intracellular junctophilin.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" is uninformative and this rests on one large-scale Y2H hit
      (JPH3) without functional characterization; per curation policy the experimental
      IPI is retained but flagged as an over-annotation rather than removed. It should not
      be treated as a core function.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "P20061; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-2557232, EBI-1055254;"
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758881
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation placing TCN1 in "Uptake of dietary cobalamins into
      enterocytes". Haptocorrin binds dietary RCbl in saliva/stomach, protecting it, so
      participation in the cobalamin transport process is correct.
    action: ACCEPT
    reason: >-
      Reactome captures TCN1's role in the gastrointestinal step of cobalamin transport;
      consistent with the core BP.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "from the acidic environment of the stomach."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758890
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation placing TCN1 in "Transport of RCbl within the body".
      Haptocorrin carries the majority of circulating plasma cobalamin and scavenges
      corrinoids for hepatobiliary clearance, so involvement in body-wide cobalamin
      transport is correct.
    action: ACCEPT
    reason: >-
      Duplicate cobalamin transport annotation from a different Reactome pathway; correct
      and core.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Binds vitamin B12 with femtomolar affinity and protects it"
- term:
    id: GO:0140355
    label: cargo receptor ligand activity
  evidence_type: EXP
  original_reference_id: PMID:22547309
  qualifier: enables
  review:
    summary: >-
      Reactome-assigned EXP annotation to "cargo receptor ligand activity", reflecting
      that cobalamin-loaded haptocorrin acts as a ligand whose complex is captured and
      endocytosed (in the liver via the asialoglycoprotein receptor). This is a
      defensible molecular-function framing of receptor-mediated clearance, but it is a
      downstream consequence of cobalamin binding rather than the protein's central
      function; the cited reference is an abstract-only review of the multistep B12
      transport pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      TCN1's ligand/cargo behaviour follows from its cobalamin binding; the annotation is
      not wrong but is secondary to the core cobalamin-binding/transport functions and
      relies on a review rather than a direct TCN1 assay, so it is kept as non-core.
    supported_by:
    - reference_id: PMID:22547309
      supporting_text: >-
        for specific uptake and transport of this molecule has evolved.
- term:
    id: GO:0140313
    label: molecular sequestering activity
  evidence_type: EXP
  original_reference_id: PMID:23846701
  qualifier: enables
  review:
    summary: >-
      Reactome-assigned EXP annotation to "molecular sequestering activity", supported by
      the crystal structure showing broad-specificity binding of cobalamin and cobinamide.
      This captures haptocorrin's role in binding/sequestering cobalamin (protecting it)
      and scavenging inactive corrinoid analogues. It is essentially a restatement of the
      cobalamin-binding function in sequestering terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      Sequestering is a valid characterization of HC's broad corrinoid binding, but it is
      a facet of the core cobalamin-binding molecular function rather than an independent
      core activity; retained as non-core.
    supported_by:
    - reference_id: PMID:23846701
      supporting_text: >-
        a similar overall structure but a different selectivity for corrinoids.
- term:
    id: GO:0140313
    label: molecular sequestering activity
  evidence_type: EXP
  original_reference_id: PMID:27411955
  qualifier: enables
  review:
    summary: >-
      Reactome-assigned EXP annotation to "molecular sequestering activity". This paper
      (holo-transcobalamin/CD320 structure) explicitly notes haptocorrin's role as a
      high-affinity plasma Cbl-binding scavenger that, unlike transcobalamin, is not
      recognized by the cellular uptake receptor CD320. Supports HC's sequestering/
      scavenging role but is a facet of cobalamin binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate molecular sequestering annotation; correctly reflects HC's scavenging role
      but is secondary to cobalamin binding, so kept as non-core.
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: >-
        Even haptocorrin (HC), a high affinity Cbl-binding protein that shares significant
        sequence and structural similarities with TC and is also circulating in the
        plasma, is not recognized by CD320.
- term:
    id: GO:0035580
    label: specific granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to specific (secondary) granule lumen. TCN1 is a major
      constituent of neutrophil secondary/specific granules and is released by neutrophil
      degranulation, so this localization is correct.
    action: ACCEPT
    reason: >-
      TCN1/haptocorrin is a well-established secondary (specific) granule protein of
      neutrophils; the granule-lumen localization is supported by UniProt tissue
      specificity and the original cloning paper.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "in response to ingestion of food. Major constituent of secondary"
    - reference_id: PMID:2777761
      supporting_text: "It is a major protein constituent of secondary granules in"
- term:
    id: GO:1904724
    label: tertiary granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to tertiary granule lumen, from the neutrophil
      degranulation pathway. TCN1 is primarily a specific/secondary granule protein;
      Reactome models it among granule-lumen proteins exocytosed during degranulation.
      Retained as a non-core localization since the primary granule assignment is the
      specific granule.
    action: KEEP_AS_NON_CORE
    reason: >-
      Granule-lumen localization is consistent with TCN1 being a neutrophil granule
      protein released by degranulation, but the tertiary-granule assignment is secondary
      to its established specific-granule localization; kept as non-core.
    supported_by:
    - reference_id: PMID:2777761
      supporting_text: "It is a major protein constituent of secondary granules in"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:16502470
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection (HDA) of TCN1 in the extracellular fluid,
      here in the aqueous phase of human colostrum. Consistent with the secreted
      localization; supports extracellular region.
    action: ACCEPT
    reason: >-
      Proteomic identification of TCN1 in an extracellular body fluid corroborates the
      secreted/extracellular localization.
    supported_by:
    - reference_id: PMID:16502470
      supporting_text: "identification of minor proteins in the aqueous phase"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3132753
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (Pancreatic proteases degrade TCN1:RCbl) placing TCN1 in
      the extracellular region, where the haptocorrin:cobalamin complex is degraded by
      pancreatic proteases in the small intestine. Correct localization.
    action: ACCEPT
    reason: >-
      Consistent with the secreted/extracellular localization of haptocorrin acting in
      the gastrointestinal lumen.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3132759
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (TCN1 binds RCbl) placing TCN1 in the extracellular region,
      where secreted haptocorrin binds free/protein-released RCbl in saliva and stomach.
      Correct localization.
    action: ACCEPT
    reason: >-
      Consistent with the secreted/extracellular localization; this is where TCN1 binds
      and protects dietary cobalamin.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "Produced by the salivary glands of the oral cavity,"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3245898
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (TCN1 binds corrinoids in the circulation) placing TCN1 in
      the extracellular region (plasma), where haptocorrin binds inactive corrinoid
      analogues for hepatobiliary clearance. Correct localization.
    action: ACCEPT
    reason: >-
      Consistent with secreted/plasma localization; corroborated by Reactome's scavenging/
      broad-corrinoid-specificity model of TCN1.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (Exocytosis of tertiary granule lumen proteins) placing
      released TCN1 in the extracellular region following neutrophil degranulation.
      Consistent with the secreted/extracellular localization.
    action: ACCEPT
    reason: >-
      TCN1 released by degranulation resides in the extracellular region; correct CC.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (Exocytosis of specific granule lumen proteins) placing
      released TCN1 in the extracellular region following neutrophil degranulation.
      Consistent with the secreted/extracellular localization.
    action: ACCEPT
    reason: >-
      TCN1 released from specific granules by degranulation resides in the extracellular
      region; correct CC.
    supported_by:
    - reference_id: file:human/TCN1/TCN1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted."
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: PMID:2777761
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to cobalamin transport from the original TCN1 cDNA cloning paper,
      which describes TCI as a member of the R-binder family of vitamin B12 binding
      proteins and a major secondary-granule protein. Supports the core cobalamin
      transport/binding role.
    action: ACCEPT
    reason: >-
      Author-stated (TAS) assignment consistent with TCN1's established role as an R-binder
      vitamin B12 binding protein; core biological process.
    supported_by:
    - reference_id: PMID:2777761
      supporting_text: "member of the R binder family of vitamin B12 binding"
core_functions:
- description: >-
    Binds cobalamin (vitamin B12) with femtomolar affinity and broad corrinoid
    specificity, binding both cobalamin and biologically inactive cobalamin analogues;
    this is the central molecular function of secreted haptocorrin.
  molecular_function:
    id: GO:0031419
    label: cobalamin binding
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: file:human/TCN1/TCN1-uniprot.txt
    supporting_text: "Binds vitamin B12 with femtomolar affinity and protects it"
  - reference_id: PMID:23846701
    supporting_text: >-
      a similar overall structure but a different selectivity for corrinoids.
- description: >-
    As a secreted cobalamin-binding glycoprotein, participates in cobalamin transport by
    binding and protecting dietary B12 from the acidic stomach, carrying the majority of
    circulating plasma B12, and scavenging inactive corrinoids for hepatobiliary
    clearance; it is not the carrier that delivers B12 into cells (that is TCN2 via CD320).
  molecular_function:
    id: GO:0031419
    label: cobalamin binding
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: file:human/TCN1/TCN1-uniprot.txt
    supporting_text: "from the acidic environment of the stomach."
  - reference_id: PMID:27411955
    supporting_text: >-
      Even haptocorrin (HC), a high affinity Cbl-binding protein that shares significant
      sequence and structural similarities with TC and is also circulating in the plasma,
      is not recognized by CD320.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      InterPro2GO pipeline reference; the IPR002157 -> cobalamin binding / cobalamin
      transport mappings are accurate for this cobalamin transport family member.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/IBA reference; the three IBA calls (extracellular region, cobalamin
      transport, cobalamin binding) correctly capture the core function of TCN1.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      SubCell "Secreted" -> extracellular region mapping is accurate for this secreted
      glycoprotein.
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by
    proteomics.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput proteomics; supports only the extracellular/secreted localization
      of TCN1 (detected in colostrum), not a specific molecular function.
- id: PMID:22547309
  title: Vitamin B12 transport from food to the body's cells--a sophisticated, multistep
    pathway.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only review of the multistep B12 transport pathway; supports the cobalamin
      transport context and the cargo/ligand framing but is not a direct TCN1 assay.
- id: PMID:23846701
  title: Structural basis for universal corrinoid recognition by the cobalamin transport
    protein haptocorrin.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structures of human haptocorrin with cyanocobalamin and cobinamide;
      directly establishes cobalamin binding and broad corrinoid specificity (core MF).
- id: PMID:27411955
  title: Structural basis of transcobalamin recognition by human CD320 receptor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text verified; explicitly states haptocorrin is a high-affinity plasma
      Cbl-binding protein NOT recognized by the cellular uptake receptor CD320,
      distinguishing HC from the delivery carrier TCN2.
- id: PMID:2777761
  title: Structure of the cDNA encoding transcobalamin I, a neutrophil granule protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original TCN1/TCI cDNA cloning paper; identifies TCI as an R-binder vitamin B12
      binding protein and a major secondary (specific) granule protein of neutrophils.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Large-scale yeast two-hybrid interactome screen; the single TCN1-JPH3 interaction
      underlies only an uninformative "protein binding" IPI with no functional follow-up.
- id: Reactome:R-HSA-3132753
  title: Pancreatic proteases degrade TCN1:RCbl
  findings: []
- id: Reactome:R-HSA-3132759
  title: TCN1 binds RCbl
  findings: []
- id: Reactome:R-HSA-3245898
  title: TCN1 binds correnoids in the circulation
  findings: []
- id: Reactome:R-HSA-6798745
  title: Exocytosis of tertiary granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6798749
  title: Exocytosis of specific granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9758881
  title: Uptake of dietary cobalamins into enterocytes
  findings: []
- id: Reactome:R-HSA-9758890
  title: Transport of RCbl within the body
  findings: []
- id: file:human/TCN1/TCN1-uniprot.txt
  title: UniProtKB entry P20061 (TCO1_HUMAN), Transcobalamin-1
  findings: []