Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation placing the secreted transcobalamin protein in the extracellular region. Consistent with the biology of a plasma cobalamin transport protein. Reason: Transcobalamin-2 is a secreted plasma protein that acts extracellularly to bind and transport cobalamin. The location is directly supported by protein purification from plasma and by the UniProt secreted subcellular location. The IBA call agrees with experimental evidence. Supporting Evidence: PMID:8443384 Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding protein in mammalian plasma that facilitates the cellular uptake of the vitamin. file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0015889 cobalamin transport	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation for involvement in cobalamin transport, the core biological process of transcobalamin-2. Reason: Cobalamin (vitamin B12) transport is the defining biological role of transcobalamin-2, which delivers newly absorbed cobalamin from the circulation to peripheral cells. This is supported by experimental evidence and by the eukaryotic cobalamin transport protein family assignment. Supporting Evidence: PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells. PMID:1708393 The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
GO:0031419 cobalamin binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation for cobalamin binding, the core molecular function of transcobalamin-2. Reason: Cobalamin binding is the direct, structurally defined molecular function of transcobalamin-2 (one cobalamin buried at the interface of its two domains). The IBA call agrees with multiple experimental (IDA) annotations and crystal structures. Supporting Evidence: PMID:16537422 One Cbl molecule in base-on conformation is buried inside the domain interface. PMID:3782074 the final preparation of holo-TCII contained 1 mol of cobalamin/mol of protein.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation mapping the UniProt "Secreted" subcellular-location keyword to the extracellular region. Reason: The SubCell mapping is correct; transcobalamin-2 is a secreted plasma protein and is located in the extracellular region. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0015889 cobalamin transport	IEA GO_REF:0000002	ACCEPT	Summary: Electronic (InterPro2GO) annotation of cobalamin transport based on the cobalamin-binding protein domain (IPR002157). Reason: The InterPro domain-based mapping to cobalamin transport is appropriate for transcobalamin-2 and is corroborated by experimental and IBA evidence for the same process. Supporting Evidence: PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
GO:0031419 cobalamin binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (ARBA/InterPro) of cobalamin binding based on the cobalamin-binding protein signature (IPR002157). Reason: The domain-based electronic call correctly assigns the core molecular function. Redundant with, and confirmed by, experimental (IDA) and IBA cobalamin-binding annotations. Supporting Evidence: PMID:16537422 One Cbl molecule in base-on conformation is buried inside the domain interface.
GO:0005515 protein binding	IPI PMID:27411955 Structural basis of transcobalamin recognition by human CD32...	MARK AS OVER ANNOTATED	Summary: IntAct/UniProt protein-binding (IPI) annotation recording the physical interaction of transcobalamin-2 with CD320 (UniProtKB:Q9NPF0), the transcobalamin receptor, demonstrated by the holo-TC:CD320 co-crystal structure. Reason: The interaction with CD320 is real and experimentally well supported, but the generic term "protein binding" is uninformative and does not capture the biology. The informative molecular function is that transcobalamin-2 acts as the ligand recognized by its endocytic uptake receptor CD320, better represented by GO:0140355 cargo receptor ligand activity (also annotated). Retained (not removed) because it is a valid experimental interaction annotation, but flagged as an over-annotation per curation guidance to avoid bare "protein binding". Supporting Evidence: PMID:27411955 Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
GO:0015889 cobalamin transport	TAS Reactome:R-HSA-9758890	ACCEPT	Summary: Reactome (TAS) annotation of cobalamin transport, from the pathway "Transport of RCbl within the body", capturing transcobalamin-2's role in moving cobalamin from the enterocyte to peripheral cells. Reason: Correctly captures the core biological process. Redundant with experimental and IBA cobalamin-transport annotations. Supporting Evidence: PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
GO:0005576 extracellular region	EXP PMID:3782074 Purification and molecular characterization of human transco...	ACCEPT	Summary: Experimental (EXP) annotation of extracellular region based on purification of transcobalamin-2 from human plasma and determination of its N-terminal sequence and secreted nature. Reason: Directly supported experimental localization. Transcobalamin-2 was purified from human plasma (Cohn fraction III) as a secreted cobalamin transport protein, consistent with an extracellular location. Supporting Evidence: PMID:3782074 purified from Cohn fraction III of human file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0140355 cargo receptor ligand activity	EXP PMID:3782074 Purification and molecular characterization of human transco...	ACCEPT	Summary: Experimental (EXP, Reactome-assigned) annotation of cargo receptor ligand activity, representing transcobalamin-2 acting as the ligand carrying cobalamin cargo that is recognized and internalized by the CD320 (TCblR) uptake receptor. Reason: This term captures the informative molecular function of transcobalamin-2 as the cargo-carrying ligand of its cell-surface uptake receptor CD320, which drives receptor-mediated endocytosis of cobalamin into cells. The ligand-for-receptor role is directly established by the holo-TC:CD320 co-crystal structure and by functional cellular-uptake assays; it is more informative than the bare "protein binding" IPI. This is a core molecular function. Supporting Evidence: PMID:27411955 transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate cell surface receptor CD320 PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3000074	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the reaction "TCN2 binds RCbl in the circulation", where secreted transcobalamin-2 binds cobalamin in plasma. Reason: Correct extracellular location for the secreted plasma protein. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0005576 extracellular region	TAS Reactome:R-HSA-3000122	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the reaction "CD320 binds extracellular TCN2:RCbl". Reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin complex captured by CD320 at the cell surface. Redundant with experimental and IBA calls. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0005576 extracellular region	TAS Reactome:R-HSA-3325546	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the disease reaction "Defective CD320 does not transport extracellular TCII:Cbl to endosome". Reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin complex. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0005576 extracellular region	TAS Reactome:R-HSA-9759202	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the reaction "LRP2-mediated TCN2:RCbl uptake and delivery to lysosome" (an alternative megalin/LRP2 uptake route, e.g. in renal tubule). Reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin complex prior to uptake. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0005576 extracellular region	TAS Reactome:R-HSA-9759209	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the reaction "LRP2 binds extracellular TCN2:RCbl". Reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin complex before receptor uptake. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000112	KEEP AS NON CORE	Summary: Reactome (TAS) annotation of plasma membrane, from "CD320-mediated TCN2:RCbl uptake and delivery to lysosome", reflecting the transcobalamin-2:cobalamin complex being bound at the cell surface by CD320 before endocytosis. Reason: Transcobalamin-2 is a soluble secreted protein, not an integral or resident plasma-membrane protein. It is only transiently at the plasma membrane as the ligand of the membrane receptor CD320 during the receptor-binding/endocytosis step. Retained as a valid step in the transport pathway but marked non-core because it is a transient, pathway-context localization rather than an intrinsic residence. Supporting Evidence: PMID:27411955 transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate cell surface receptor CD320
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000122	KEEP AS NON CORE	Summary: Reactome (TAS) annotation of plasma membrane, from "CD320 binds extracellular TCN2:RCbl", reflecting the transcobalamin-2:cobalamin complex engaging its cell-surface receptor. Reason: As above, transcobalamin-2 is a secreted soluble protein that only transiently associates with the plasma membrane as the ligand of CD320 during receptor binding. Retained as a valid pathway step but marked non-core rather than an intrinsic localization. Supporting Evidence: PMID:27411955 Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-3000112	KEEP AS NON CORE	Summary: Reactome (TAS) annotation of lysosomal lumen, from "CD320-mediated TCN2:RCbl uptake and delivery to lysosome", where the internalized transcobalamin-2:cobalamin complex is delivered to the lysosome. Reason: The transcobalamin-2:cobalamin complex is trafficked to the lysosome, where transcobalamin-2 is degraded to release cobalamin. This is the terminal destination of the transport pathway, not an intrinsic steady-state location of the protein. Retained as a valid pathway step but marked non-core. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt FUNCTION: Primary vitamin B12-binding and transport protein. Delivers
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-3000263	KEEP AS NON CORE	Summary: Reactome (TAS) annotation of lysosomal lumen, from "TCN2:RCbl is degraded to release RCbl", where a lysosomal protease degrades transcobalamin-2 to liberate cobalamin. Reason: Represents the terminal lysosomal degradation step of the transport pathway, not an intrinsic localization of transcobalamin-2. Retained as a valid pathway step but marked non-core. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt FUNCTION: Primary vitamin B12-binding and transport protein. Delivers
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-9759202	KEEP AS NON CORE	Summary: Reactome (TAS) annotation of lysosomal lumen, from "LRP2-mediated TCN2:RCbl uptake and delivery to lysosome" (LRP2/megalin uptake route). Reason: As with the CD320 route, the internalized complex is delivered to the lysosome for degradation and cobalamin release; this is a terminal pathway destination rather than an intrinsic localization. Retained as a valid pathway step but marked non-core. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt FUNCTION: Primary vitamin B12-binding and transport protein. Delivers
GO:0005576 extracellular region	IDA PMID:8443384 Functional human transcobalamin II isoproteins are secreted ...	ACCEPT	Summary: Experimental (IDA) annotation of extracellular region; recombinant transcobalamin-2 was constitutively secreted by insect cells, consistent with its native secretion. Reason: Directly supported experimental localization. Recombinant transcobalamin-2 was secreted into the culture medium and did not accumulate intracellularly, mirroring its secretion by cultured human endothelial cells. Supporting Evidence: PMID:8443384 Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding protein in mammalian plasma that facilitates the cellular uptake of the vitamin. file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0015889 cobalamin transport	IDA PMID:8443384 Functional human transcobalamin II isoproteins are secreted ...	ACCEPT	Summary: Experimental (IDA) annotation of cobalamin transport; recombinant transcobalamin-2 bound cobalamin and facilitated its uptake into cells via the plasma-membrane TCII-Cbl receptor. Reason: Directly demonstrated core biological process. Functional recombinant transcobalamin-2 bound Cbl and facilitated its uptake into K562 cells by binding the TCII-Cbl receptor on the plasma membrane. Supporting Evidence: PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
GO:0031419 cobalamin binding	IDA PMID:27411955 Structural basis of transcobalamin recognition by human CD32...	ACCEPT	Summary: Experimental (IDA) annotation of cobalamin binding; the holo-TC:CD320 co-crystal structure resolved cobalamin bound to transcobalamin-2. Reason: Directly demonstrated core molecular function. The 2.1 Angstrom co-crystal structure of holo-transcobalamin-2 in complex with CD320 shows cobalamin bound to transcobalamin-2, with the cobalt of Cbl identified in the electron density. Supporting Evidence: PMID:27411955 Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
GO:0031419 cobalamin binding	IDA PMID:8443384 Functional human transcobalamin II isoproteins are secreted ...	ACCEPT	Summary: Experimental (IDA) annotation of cobalamin binding; recombinant transcobalamin-2 bound cobalamin. Reason: Directly demonstrated core molecular function. Functional recombinant transcobalamin-2 cross-reacted with antiserum to native TCII and bound Cbl. Supporting Evidence: PMID:8443384 binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3299657	ACCEPT	Summary: Reactome (TAS) annotation of extracellular region, from the disease reaction "Defective TCII does not bind Cbl in the circulation". Reason: Correct extracellular location for the secreted plasma protein. Redundant with experimental and IBA calls for the same term. Supporting Evidence: file:human/TCN2/TCN2-uniprot.txt SUBCELLULAR LOCATION: Secreted
GO:0031419 cobalamin binding	IDA PMID:16537422 Structural basis for mammalian vitamin B12 transport by tran...	ACCEPT	Summary: Experimental (IDA) annotation of cobalamin binding; the crystal structure of human holo-transcobalamin resolved one cobalamin buried at the interface of its two domains. Reason: Directly demonstrated core molecular function with atomic-resolution structural evidence. The holo-TC structure shows a single Cbl in base-on conformation buried at the domain interface, with a barrel histidine as the axial ligand. Supporting Evidence: PMID:16537422 One Cbl molecule in base-on conformation is buried inside the domain interface.
GO:0005576 extracellular region	TAS PMID:1708393 The cDNA sequence and the deduced amino acid sequence of hum...	ACCEPT	Summary: Traceable-author-statement (TAS) annotation of extracellular region; the cDNA encodes a secreted 409-residue protein with an 18-residue leader peptide, secreted by endothelial cells. Reason: Correct extracellular location supported by the cloned cDNA encoding a signal peptide and secreted mature protein, and by demonstrated secretion from human umbilical vein endothelial cells. Redundant with experimental and IBA calls for the same term. Supporting Evidence: PMID:1708393 The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
GO:0015889 cobalamin transport	TAS PMID:3782074 Purification and molecular characterization of human transco...	ACCEPT	Summary: Traceable-author-statement (TAS) annotation of cobalamin transport, from the characterization of transcobalamin-2 as the plasma cobalamin transport protein. Reason: Correctly captures the core biological process. Transcobalamin-2 was purified as the plasma holo-cobalamin transport protein (1 mol cobalamin/mol protein). Redundant with experimental and IBA cobalamin-transport annotations. Supporting Evidence: PMID:3782074 the final preparation of holo-TCII contained 1 mol of cobalamin/mol of protein.

Core Functions

Binds vitamin B12 (cobalamin) with 1:1 stoichiometry as the primary plasma cobalamin-binding protein, sequestering a single cobalamin molecule at the interface of its two structural domains.

Molecular Function:

cobalamin binding

Supporting Evidence:

PMID:16537422
One Cbl molecule in base-on conformation is buried inside the domain interface.
PMID:3782074
the final preparation of holo-TCII contained 1 mol of cobalamin/mol of protein.

Acts as the cargo-carrying ligand recognized by the cell-surface uptake receptor CD320 (TCblR), enabling receptor-mediated endocytosis of the transcobalamin-cobalamin complex and thereby delivery of vitamin B12 into cells.

Molecular Function:

cargo receptor ligand activity

Directly Involved In:

cobalamin transport

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:27411955
transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate cell surface receptor CD320
PMID:8443384
binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.

As a secreted plasma protein, transports newly absorbed cobalamin from the circulation to peripheral cells throughout the body, the physiologically essential route supplying vitamin B12 to tissues.

Molecular Function:

cobalamin binding

Directly Involved In:

cobalamin transport

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:1708393
The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
PMID:8443384
Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding protein in mammalian plasma that facilitates the cellular uptake of the vitamin.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16537422

Structural basis for mammalian vitamin B12 transport by transcobalamin.

The crystal structure of human holo-transcobalamin reveals a two-domain architecture with one cobalamin buried in base-on conformation at the domain interface, defining the structural basis of cobalamin binding.

PMID:1708393

The cDNA sequence and the deduced amino acid sequence of human transcobalamin II show homology with rat intrinsic factor and human transcobalamin I.

The transcobalamin-2 cDNA encodes an 18-residue leader peptide and a secreted 409-residue protein; the protein is a plasma cobalamin-binding protein secreted by endothelial cells and mediates cellular uptake of cobalamin.

PMID:27411955

Structural basis of transcobalamin recognition by human CD320 receptor.

The holo-TC:CD320 co-crystal structure shows transcobalamin-2, carrying bound cobalamin, engaging the LDLR-A domains of the cell-surface receptor CD320, the interaction that drives receptor-mediated cellular uptake of vitamin B12; binding is Ca2+-dependent and reduced at endosomal (low) pH.

PMID:3782074

Purification and molecular characterization of human transcobalamin II.

Transcobalamin-2 was purified from human plasma as a secreted holo-protein containing one cobalamin per protein molecule, establishing its extracellular localization and 1:1 cobalamin binding.

PMID:8443384

Functional human transcobalamin II isoproteins are secreted by insect cells using the baculovirus expression system.

Recombinant transcobalamin-2 is constitutively secreted, binds cobalamin, and facilitates cobalamin uptake into cells by binding the plasma-membrane TCII-Cbl receptor, directly demonstrating its cobalamin-binding and transport functions.

file:human/TCN2/TCN2-uniprot.txt

UniProtKB P20062 (TCO2_HUMAN) Transcobalamin-2

UniProt describes transcobalamin-2 as the primary vitamin B12-binding and transport protein that delivers cobalamin to cells, is secreted, and interacts with CD320 via its LDL-receptor class A domains; loss of function causes transcobalamin II deficiency (TCN2D).

Reactome:R-HSA-3000074

TCN2 binds RCbl in the circulation

Reactome:R-HSA-3000112

CD320-mediated TCN2:RCbl uptake and delivery to lysosome

Reactome:R-HSA-3000122

CD320 binds extracellular TCN2:RCbl

Reactome:R-HSA-3000263

TCN2:RCbl is degraded to release RCbl

Reactome:R-HSA-3299657

Defective TCII does not bind Cbl in the circulation

Reactome:R-HSA-3325546

Defective CD320 does not transport extracellular TCII:Cbl to endosome

Reactome:R-HSA-9758890

Transport of RCbl within the body

Reactome:R-HSA-9759202

LRP2-mediated TCN2:RCbl uptake and delivery to lysosome

Reactome:R-HSA-9759209

LRP2 binds extracellular TCN2:RCbl

Suggested Experiments

Experiment: Quantify the relative contribution of CD320 versus LRP2/megalin to tissue cobalamin delivery using tissue-specific knockout models and labelled-cobalamin uptake assays.

Experiment: Structural and kinetic characterization of cobalamin loading onto apo-transcobalamin-2, including whether an enterocyte export factor is required for efficient loading.

📚 Additional Documentation

Notes

(TCN2-notes.md)

TCN2 (Transcobalamin-2 / Transcobalamin II) review notes

UniProt: P20062 (TCO2_HUMAN). HGNC:11653. Gene TCN2 (synonym TC2). 427 aa precursor;
signal peptide 1-18, mature chain 19-427. Secreted. Chromosome 22.
Deep research: falcon out of credits (HTTP 402); no deep-research file. Grounded in
UniProt record, GOA, and cached PMIDs/Reactome.

Core biology (verified)

TCN2 is the primary plasma vitamin B12 (cobalamin, Cbl)-binding and transport
protein. It is secreted (notably by vascular endothelial cells), circulates in
plasma, binds newly absorbed cobalamin exported from the enterocyte, and delivers it to
peripheral cells. The holo-TC (TC:Cbl) complex is captured from plasma by the ubiquitous
cell-surface receptor CD320 (TCblR), a member of the LDL-receptor family, and taken
up by receptor-mediated endocytosis; TC:Cbl is delivered to lysosomes where TC is
degraded and Cbl released for downstream cofactor use (methylcobalamin for methionine
synthase; adenosylcobalamin for methylmalonyl-CoA mutase). This CD320 route is the
physiologically essential pathway supplying B12 to tissues. TCN2 is not an enzyme;
its molecular function is cobalamin binding, enabling cobalamin transport / acting as
the ligand for its uptake receptor.

Function (UniProt CC): "Primary vitamin B12-binding and transport protein. Delivers
cobalamin to cells." [ECO:0000269|PubMed:8443384]
SUBUNIT: "Interacts with CD320 (via LDL-receptor class A domains)."
[ECO:0000269|PubMed:27411955]
SUBCELLULAR LOCATION: "Secreted" [ECO:0000269|PubMed:3782074, 8443384]
SIMILARITY: "Belongs to the eukaryotic cobalamin transport proteins family."

Evidence from cached publications

PMID:3782074 (Quadros et al. 1986, JBC) — Purification & molecular characterization
of human TCII from plasma; determined N-terminal 19 aa; holo-TCII contained 1 mol
cobalamin/mol protein; single 43 kDa polypeptide. UniProt RP: "PROTEIN SEQUENCE OF
19-37, AND SUBCELLULAR LOCATION." Basis for secreted/extracellular localization and
cobalamin binding (1:1). Abstract-only cache.
Verbatim: "the final preparation of holo-TCII contained 1 mol of cobalamin/mol of
protein."
PMID:8443384 (Quadros et al. 1993, Blood) — Recombinant human TCII secreted by
insect (baculovirus) cells; binds Cbl and facilitates cellular uptake by binding to
the TCII-Cbl receptor on the plasma membrane of K562 cells. UniProt FUNCTION source.
Verbatim: "Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding protein
in mammalian plasma that facilitates the cellular uptake of the vitamin."
Verbatim: "binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding
to the receptor for TCII-Cbl on the plasma membrane of K562 cells."
PMID:16537422 (Wuerges et al. 2006, PNAS) — Crystal structures of human & bovine
holo-TC; two-domain architecture (N-terminal alpha6-alpha6 barrel + smaller C-terminal
domain); one Cbl buried at the domain interface; base-on conformation; His of barrel
becomes axial ligand. Direct structural evidence for cobalamin binding.
Verbatim: "One Cbl molecule in base-on conformation is buried inside the domain
interface."
Verbatim: "the plasma transport, and cellular uptake uses cell surface receptors and
three Cbl-transporting proteins, haptocorrin, intrinsic factor, and transcobalamin
(TC)." [note: exact substring is "plasma transport, and cellular uptake"]
PMID:27411955 (Alam et al. 2016, Nat Commun) — Crystal structure of human holo-TC
in complex with CD320 ectodomain. Establishes TC as the ligand captured by CD320 for
receptor-mediated endocytosis; pH-dependent release in endosome. Full text available.
Basis for the IPI protein-binding (interactor CD320/Q9NPF0) and cargo-receptor-ligand.
Verbatim: "Cellular uptake of vitamin B12 (cobalamin) requires capture of
transcobalamin (TC) from the plasma by CD320, a ubiquitous cell surface receptor of
the LDLR family."
Verbatim: "transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated
endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate
cell surface receptor CD320"
PMID:1708393 (Platica et al. 1991, JBC) — cDNA/deduced aa sequence; leader peptide
18 aa + secreted protein of 409 aa; homology to TCI and rat intrinsic factor. TAS
basis (via PINC) for extracellular localization. Abstract-only.
Verbatim: "The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by
transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by human
umbilical vein endothelial (HUVE) cells."

GOA annotations (29 GOA rows → 27 stub entries; grouped)

MF:
- GO:0031419 cobalamin binding — IBA (GO_REF:0000033), IEA (GO_REF:0000120), IDA
x3 (PMID:27411955, PMID:8443384, PMID:16537422). CORE. ACCEPT experimental/IBA.
- GO:0140355 cargo receptor ligand activity — EXP (PMID:3782074, assigned Reactome).
Captures TC being the ligand recognized by CD320 for endocytic uptake. Supportable
(Alam 2016 structural + Reactome CD320 model). ACCEPT (core—ligand for its uptake
receptor). Note: EXP reference PMID:3782074 is the purification paper; the functional
ligand-for-receptor role is directly shown by PMID:27411955/8443384.
- GO:0005515 protein binding — IPI (PMID:27411955), interactor UniProtKB:Q9NPF0 (CD320).
Bare "protein binding" — uninformative per policy → MARK_AS_OVER_ANNOTATED (the
informative capture of the CD320 interaction is GO:0140355 cargo receptor ligand
activity). Do NOT REMOVE (experimental IPI).

BP:
- GO:0015889 cobalamin transport — IBA (GO_REF:0000033), IEA (GO_REF:0000002 InterPro),
TAS (Reactome R-HSA-9758890), IDA (PMID:8443384), TAS (PMID:3782074). CORE. ACCEPT.

CC:
- GO:0005576 extracellular region — IBA (GO_REF:0000033), IEA (GO_REF:0000044
SubCell), EXP (PMID:3782074), IDA (PMID:8443384), TAS PMID:1708393, TAS Reactome
(R-HSA-3000074, 3000122, 3325546, 9759202, 9759209, 3299657). Secreted protein → CORE
location. ACCEPT experimental; ACCEPT/route-context for TAS/IEA/IBA.
- GO:0005886 plasma membrane — TAS Reactome (R-HSA-3000112, 3000122). TCN2 is not itself
a PM protein; it is transiently AT the PM as the ligand of CD320 during receptor
binding/endocytosis. KEEP_AS_NON_CORE (transient transport-pathway localization, not a
resident membrane protein).
- GO:0043202 lysosomal lumen — TAS Reactome (R-HSA-3000112, 3000263, 9759202). TC:Cbl is
delivered to lysosomes and degraded there. KEEP_AS_NON_CORE (transient
transport-pathway localization; the terminal degradation compartment).

Core function summary

Cobalamin (vitamin B12) binding — GO:0031419 (MF). 1:1 holo-TC; structurally defined.
Cobalamin transport — GO:0015889 (BP). Delivers newly absorbed B12 to peripheral cells.
Cargo receptor ligand activity — GO:0140355 (MF). TC:Cbl is the ligand captured by
CD320 (TCblR) for receptor-mediated endocytic uptake.
Location: extracellular region GO:0005576 (secreted plasma protein).

Disease

Transcobalamin II deficiency (TCN2D, MIM:275350): autosomal recessive; early-infancy
failure to thrive, megaloblastic anemia, pancytopenia, agammaglobulinemia,
immunodeficiency/recurrent infections, methylmalonic aciduria; untreated → neurological
(psychomotor/mental developmental delay). (UniProt DISEASE, PMID:14632784, 19373259,
32841161, 33023511.)

📄 View Raw YAML

id: P20062
gene_symbol: TCN2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Transcobalamin-2 (transcobalamin II, TC II) is the primary secreted plasma
  cobalamin (vitamin B12)-binding and transport protein. It is a soluble, non-glycosylated
  427-residue precursor (18-residue signal peptide, mature chain 19-427) secreted into
  the circulation, notably by vascular endothelial cells. In plasma it binds a single
  cobalamin molecule (holo-TC, 1:1 stoichiometry) that has been newly absorbed and exported
  from the enterocyte, and delivers it to cells throughout the body. The transcobalamin-cobalamin
  complex is captured from plasma by the ubiquitous cell-surface receptor CD320 (TCblR),
  a member of the LDL-receptor family, and is internalized by receptor-mediated endocytosis;
  the complex is delivered to lysosomes where transcobalamin is degraded and cobalamin
  is released for use as a cofactor (as methylcobalamin by methionine synthase and as
  adenosylcobalamin by methylmalonyl-CoA mutase). This CD320-dependent route is the physiologically
  essential pathway that supplies vitamin B12 to peripheral tissues. Transcobalamin-2
  is not an enzyme; its molecular function is cobalamin binding, and it acts as the ligand
  recognized by its uptake receptor. Loss-of-function causes autosomal recessive transcobalamin
  II deficiency (TCN2D), which presents in early infancy with failure to thrive, severe
  megaloblastic anemia, pancytopenia, immunodeficiency with recurrent infections, and
  methylmalonic aciduria (with homocystinuria), and, if untreated, neurological and developmental
  impairment.
alternative_products:
- name: '1'
  id: P20062-1
- name: '2'
  id: P20062-2
  sequence_note: VSP_043711
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) annotation placing the secreted transcobalamin protein
      in the extracellular region. Consistent with the biology of a plasma cobalamin
      transport protein.
    action: ACCEPT
    reason: Transcobalamin-2 is a secreted plasma protein that acts extracellularly to
      bind and transport cobalamin. The location is directly supported by protein purification
      from plasma and by the UniProt secreted subcellular location. The IBA call agrees
      with experimental evidence.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding
        protein in mammalian plasma that facilitates the cellular uptake of the vitamin.
    - reference_id: file:human/TCN2/TCN2-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) annotation for involvement in cobalamin transport, the
      core biological process of transcobalamin-2.
    action: ACCEPT
    reason: Cobalamin (vitamin B12) transport is the defining biological role of transcobalamin-2,
      which delivers newly absorbed cobalamin from the circulation to peripheral cells.
      This is supported by experimental evidence and by the eukaryotic cobalamin transport
      protein family assignment.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
    - reference_id: PMID:1708393
      supporting_text: The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated
        by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation for cobalamin binding, the core molecular function
      of transcobalamin-2.
    action: ACCEPT
    reason: Cobalamin binding is the direct, structurally defined molecular function of
      transcobalamin-2 (one cobalamin buried at the interface of its two domains). The
      IBA call agrees with multiple experimental (IDA) annotations and crystal structures.
    supported_by:
    - reference_id: PMID:16537422
      supporting_text: One Cbl molecule in base-on conformation is buried inside the domain
        interface.
    - reference_id: PMID:3782074
      supporting_text: the final preparation of holo-TCII contained 1 mol of cobalamin/mol
        of protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation mapping the UniProt "Secreted" subcellular-location
      keyword to the extracellular region.
    action: ACCEPT
    reason: The SubCell mapping is correct; transcobalamin-2 is a secreted plasma protein
      and is located in the extracellular region. Redundant with experimental and IBA
      calls for the same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-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: Electronic (InterPro2GO) annotation of cobalamin transport based on the cobalamin-binding
      protein domain (IPR002157).
    action: ACCEPT
    reason: The InterPro domain-based mapping to cobalamin transport is appropriate for
      transcobalamin-2 and is corroborated by experimental and IBA evidence for the same
      process.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (ARBA/InterPro) of cobalamin binding based on the cobalamin-binding
      protein signature (IPR002157).
    action: ACCEPT
    reason: The domain-based electronic call correctly assigns the core molecular function.
      Redundant with, and confirmed by, experimental (IDA) and IBA cobalamin-binding annotations.
    supported_by:
    - reference_id: PMID:16537422
      supporting_text: One Cbl molecule in base-on conformation is buried inside the domain
        interface.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27411955
  qualifier: enables
  review:
    summary: IntAct/UniProt protein-binding (IPI) annotation recording the physical interaction
      of transcobalamin-2 with CD320 (UniProtKB:Q9NPF0), the transcobalamin receptor,
      demonstrated by the holo-TC:CD320 co-crystal structure.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction with CD320 is real and experimentally well supported, but the
      generic term "protein binding" is uninformative and does not capture the biology.
      The informative molecular function is that transcobalamin-2 acts as the ligand recognized
      by its endocytic uptake receptor CD320, better represented by GO:0140355 cargo receptor
      ligand activity (also annotated). Retained (not removed) because it is a valid experimental
      interaction annotation, but flagged as an over-annotation per curation guidance to
      avoid bare "protein binding".
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin
        (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
- 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 of cobalamin transport, from the pathway "Transport
      of RCbl within the body", capturing transcobalamin-2's role in moving cobalamin
      from the enterocyte to peripheral cells.
    action: ACCEPT
    reason: Correctly captures the core biological process. Redundant with experimental
      and IBA cobalamin-transport annotations.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:3782074
  qualifier: located_in
  review:
    summary: Experimental (EXP) annotation of extracellular region based on purification
      of transcobalamin-2 from human plasma and determination of its N-terminal sequence
      and secreted nature.
    action: ACCEPT
    reason: Directly supported experimental localization. Transcobalamin-2 was purified
      from human plasma (Cohn fraction III) as a secreted cobalamin transport protein,
      consistent with an extracellular location.
    supported_by:
    - reference_id: PMID:3782074
      supporting_text: purified from Cohn fraction III of human
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0140355
    label: cargo receptor ligand activity
  evidence_type: EXP
  original_reference_id: PMID:3782074
  qualifier: enables
  review:
    summary: Experimental (EXP, Reactome-assigned) annotation of cargo receptor ligand
      activity, representing transcobalamin-2 acting as the ligand carrying cobalamin cargo
      that is recognized and internalized by the CD320 (TCblR) uptake receptor.
    action: ACCEPT
    reason: This term captures the informative molecular function of transcobalamin-2 as
      the cargo-carrying ligand of its cell-surface uptake receptor CD320, which drives
      receptor-mediated endocytosis of cobalamin into cells. The ligand-for-receptor role
      is directly established by the holo-TC:CD320 co-crystal structure and by functional
      cellular-uptake assays; it is more informative than the bare "protein binding" IPI.
      This is a core molecular function.
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated
        endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate
        cell surface receptor CD320
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000074
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the reaction "TCN2
      binds RCbl in the circulation", where secreted transcobalamin-2 binds cobalamin
      in plasma.
    action: ACCEPT
    reason: Correct extracellular location for the secreted plasma protein. Redundant with
      experimental and IBA calls for the same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000122
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the reaction "CD320
      binds extracellular TCN2:RCbl".
    action: ACCEPT
    reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin
      complex captured by CD320 at the cell surface. Redundant with experimental and IBA
      calls.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3325546
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the disease reaction
      "Defective CD320 does not transport extracellular TCII:Cbl to endosome".
    action: ACCEPT
    reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin
      complex. Redundant with experimental and IBA calls for the same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759202
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the reaction "LRP2-mediated
      TCN2:RCbl uptake and delivery to lysosome" (an alternative megalin/LRP2 uptake route,
      e.g. in renal tubule).
    action: ACCEPT
    reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin
      complex prior to uptake. Redundant with experimental and IBA calls for the same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759209
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the reaction "LRP2
      binds extracellular TCN2:RCbl".
    action: ACCEPT
    reason: Correct extracellular location for the secreted transcobalamin-2:cobalamin
      complex before receptor uptake. Redundant with experimental and IBA calls for the
      same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000112
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of plasma membrane, from "CD320-mediated TCN2:RCbl
      uptake and delivery to lysosome", reflecting the transcobalamin-2:cobalamin complex
      being bound at the cell surface by CD320 before endocytosis.
    action: KEEP_AS_NON_CORE
    reason: Transcobalamin-2 is a soluble secreted protein, not an integral or resident
      plasma-membrane protein. It is only transiently at the plasma membrane as the ligand
      of the membrane receptor CD320 during the receptor-binding/endocytosis step. Retained
      as a valid step in the transport pathway but marked non-core because it is a transient,
      pathway-context localization rather than an intrinsic residence.
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated
        endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate
        cell surface receptor CD320
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000122
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of plasma membrane, from "CD320 binds extracellular
      TCN2:RCbl", reflecting the transcobalamin-2:cobalamin complex engaging its cell-surface
      receptor.
    action: KEEP_AS_NON_CORE
    reason: As above, transcobalamin-2 is a secreted soluble protein that only transiently
      associates with the plasma membrane as the ligand of CD320 during receptor binding.
      Retained as a valid pathway step but marked non-core rather than an intrinsic localization.
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin
        (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000112
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of lysosomal lumen, from "CD320-mediated TCN2:RCbl
      uptake and delivery to lysosome", where the internalized transcobalamin-2:cobalamin
      complex is delivered to the lysosome.
    action: KEEP_AS_NON_CORE
    reason: The transcobalamin-2:cobalamin complex is trafficked to the lysosome, where
      transcobalamin-2 is degraded to release cobalamin. This is the terminal destination
      of the transport pathway, not an intrinsic steady-state location of the protein.
      Retained as a valid pathway step but marked non-core.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "FUNCTION: Primary vitamin B12-binding and transport protein. Delivers"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000263
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of lysosomal lumen, from "TCN2:RCbl is degraded
      to release RCbl", where a lysosomal protease degrades transcobalamin-2 to liberate
      cobalamin.
    action: KEEP_AS_NON_CORE
    reason: Represents the terminal lysosomal degradation step of the transport pathway,
      not an intrinsic localization of transcobalamin-2. Retained as a valid pathway step
      but marked non-core.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "FUNCTION: Primary vitamin B12-binding and transport protein. Delivers"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759202
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of lysosomal lumen, from "LRP2-mediated TCN2:RCbl
      uptake and delivery to lysosome" (LRP2/megalin uptake route).
    action: KEEP_AS_NON_CORE
    reason: As with the CD320 route, the internalized complex is delivered to the lysosome
      for degradation and cobalamin release; this is a terminal pathway destination rather
      than an intrinsic localization. Retained as a valid pathway step but marked non-core.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "FUNCTION: Primary vitamin B12-binding and transport protein. Delivers"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:8443384
  qualifier: located_in
  review:
    summary: Experimental (IDA) annotation of extracellular region; recombinant transcobalamin-2
      was constitutively secreted by insect cells, consistent with its native secretion.
    action: ACCEPT
    reason: Directly supported experimental localization. Recombinant transcobalamin-2
      was secreted into the culture medium and did not accumulate intracellularly, mirroring
      its secretion by cultured human endothelial cells.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding
        protein in mammalian plasma that facilitates the cellular uptake of the vitamin.
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IDA
  original_reference_id: PMID:8443384
  qualifier: involved_in
  review:
    summary: Experimental (IDA) annotation of cobalamin transport; recombinant transcobalamin-2
      bound cobalamin and facilitated its uptake into cells via the plasma-membrane TCII-Cbl
      receptor.
    action: ACCEPT
    reason: Directly demonstrated core biological process. Functional recombinant transcobalamin-2
      bound Cbl and facilitated its uptake into K562 cells by binding the TCII-Cbl receptor
      on the plasma membrane.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IDA
  original_reference_id: PMID:27411955
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation of cobalamin binding; the holo-TC:CD320 co-crystal
      structure resolved cobalamin bound to transcobalamin-2.
    action: ACCEPT
    reason: Directly demonstrated core molecular function. The 2.1 Angstrom co-crystal
      structure of holo-transcobalamin-2 in complex with CD320 shows cobalamin bound to
      transcobalamin-2, with the cobalt of Cbl identified in the electron density.
    supported_by:
    - reference_id: PMID:27411955
      supporting_text: Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin
        (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family.
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IDA
  original_reference_id: PMID:8443384
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation of cobalamin binding; recombinant transcobalamin-2
      bound cobalamin.
    action: ACCEPT
    reason: Directly demonstrated core molecular function. Functional recombinant transcobalamin-2
      cross-reacted with antiserum to native TCII and bound Cbl.
    supported_by:
    - reference_id: PMID:8443384
      supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells
        by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3299657
  qualifier: located_in
  review:
    summary: Reactome (TAS) annotation of extracellular region, from the disease reaction
      "Defective TCII does not bind Cbl in the circulation".
    action: ACCEPT
    reason: Correct extracellular location for the secreted plasma protein. Redundant with
      experimental and IBA calls for the same term.
    supported_by:
    - reference_id: file:human/TCN2/TCN2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Secreted"
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IDA
  original_reference_id: PMID:16537422
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation of cobalamin binding; the crystal structure
      of human holo-transcobalamin resolved one cobalamin buried at the interface of its
      two domains.
    action: ACCEPT
    reason: Directly demonstrated core molecular function with atomic-resolution structural
      evidence. The holo-TC structure shows a single Cbl in base-on conformation buried
      at the domain interface, with a barrel histidine as the axial ligand.
    supported_by:
    - reference_id: PMID:16537422
      supporting_text: One Cbl molecule in base-on conformation is buried inside the domain
        interface.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: PMID:1708393
  qualifier: located_in
  review:
    summary: Traceable-author-statement (TAS) annotation of extracellular region; the cDNA
      encodes a secreted 409-residue protein with an 18-residue leader peptide, secreted
      by endothelial cells.
    action: ACCEPT
    reason: Correct extracellular location supported by the cloned cDNA encoding a signal
      peptide and secreted mature protein, and by demonstrated secretion from human umbilical
      vein endothelial cells. Redundant with experimental and IBA calls for the same term.
    supported_by:
    - reference_id: PMID:1708393
      supporting_text: The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated
        by transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: PMID:3782074
  qualifier: involved_in
  review:
    summary: Traceable-author-statement (TAS) annotation of cobalamin transport, from the
      characterization of transcobalamin-2 as the plasma cobalamin transport protein.
    action: ACCEPT
    reason: Correctly captures the core biological process. Transcobalamin-2 was purified
      as the plasma holo-cobalamin transport protein (1 mol cobalamin/mol protein). Redundant
      with experimental and IBA cobalamin-transport annotations.
    supported_by:
    - reference_id: PMID:3782074
      supporting_text: the final preparation of holo-TCII contained 1 mol of cobalamin/mol
        of protein.
core_functions:
- description: Binds vitamin B12 (cobalamin) with 1:1 stoichiometry as the primary plasma
    cobalamin-binding protein, sequestering a single cobalamin molecule at the interface
    of its two structural domains.
  molecular_function:
    id: GO:0031419
    label: cobalamin binding
  supported_by:
  - reference_id: PMID:16537422
    supporting_text: One Cbl molecule in base-on conformation is buried inside the domain
      interface.
  - reference_id: PMID:3782074
    supporting_text: the final preparation of holo-TCII contained 1 mol of cobalamin/mol
      of protein.
- description: Acts as the cargo-carrying ligand recognized by the cell-surface uptake
    receptor CD320 (TCblR), enabling receptor-mediated endocytosis of the transcobalamin-cobalamin
    complex and thereby delivery of vitamin B12 into cells.
  molecular_function:
    id: GO:0140355
    label: cargo receptor ligand activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:27411955
    supporting_text: transcobalamin (TC)-bound Cbl is transported into cells by receptor-mediated
      endocytosis, which requires Ca2+-dependent complex formation of TC with its cognate
      cell surface receptor CD320
  - reference_id: PMID:8443384
    supporting_text: binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by
      binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells.
- description: As a secreted plasma protein, transports newly absorbed cobalamin from the
    circulation to peripheral cells throughout the body, the physiologically essential
    route supplying vitamin B12 to tissues.
  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: PMID:1708393
    supporting_text: The cellular uptake of cobalamin (Cbl, vitamin B12) is mediated by
      transcobalamin II (TCII), a plasma protein that binds Cbl and is secreted by
  - reference_id: PMID:8443384
    supporting_text: Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding
      protein in mammalian plasma that facilitates the cellular uptake of the vitamin.
proposed_new_terms: []
suggested_questions:
- question: Beyond CD320, how much does the LRP2/megalin-mediated route (e.g. in the renal
    tubule) contribute to transcobalamin-cobalamin reuptake and tissue cobalamin delivery
    in vivo?
- question: Does apo-transcobalamin-2 have a distinct physiological function or receptor
    engagement compared with holo-transcobalamin-2?
suggested_experiments:
- description: Quantify the relative contribution of CD320 versus LRP2/megalin to tissue
    cobalamin delivery using tissue-specific knockout models and labelled-cobalamin uptake
    assays.
- description: Structural and kinetic characterization of cobalamin loading onto apo-transcobalamin-2,
    including whether an enterocyte export factor is required for efficient loading.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- 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: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16537422
  title: Structural basis for mammalian vitamin B12 transport by transcobalamin.
  findings:
  - statement: The crystal structure of human holo-transcobalamin reveals a two-domain
      architecture with one cobalamin buried in base-on conformation at the domain interface,
      defining the structural basis of cobalamin binding.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; primary structural evidence (PDB 2BB5) for cobalamin
      binding by transcobalamin-2. Abstract-only in cache but supporting quotes are verbatim
      from the abstract.
- id: PMID:1708393
  title: The cDNA sequence and the deduced amino acid sequence of human transcobalamin
    II show homology with rat intrinsic factor and human transcobalamin I.
  findings:
  - statement: The transcobalamin-2 cDNA encodes an 18-residue leader peptide and a secreted
      409-residue protein; the protein is a plasma cobalamin-binding protein secreted by
      endothelial cells and mediates cellular uptake of cobalamin.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes secreted nature and cobalamin-transport
      role. Abstract-only in cache.
- id: PMID:27411955
  title: Structural basis of transcobalamin recognition by human CD320 receptor.
  findings:
  - statement: The holo-TC:CD320 co-crystal structure shows transcobalamin-2, carrying
      bound cobalamin, engaging the LDLR-A domains of the cell-surface receptor CD320,
      the interaction that drives receptor-mediated cellular uptake of vitamin B12; binding
      is Ca2+-dependent and reduced at endosomal (low) pH.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; full text available. Basis for both the protein-binding
      IPI (interactor CD320/Q9NPF0) and the cargo receptor ligand activity.
- id: PMID:3782074
  title: Purification and molecular characterization of human transcobalamin II.
  findings:
  - statement: Transcobalamin-2 was purified from human plasma as a secreted holo-protein
      containing one cobalamin per protein molecule, establishing its extracellular localization
      and 1:1 cobalamin binding.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; source of the EXP extracellular-region and cargo receptor
      ligand annotations. Abstract-only in cache.
- id: PMID:8443384
  title: Functional human transcobalamin II isoproteins are secreted by insect cells using
    the baculovirus expression system.
  findings:
  - statement: Recombinant transcobalamin-2 is constitutively secreted, binds cobalamin,
      and facilitates cobalamin uptake into cells by binding the plasma-membrane TCII-Cbl
      receptor, directly demonstrating its cobalamin-binding and transport functions.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; UniProt FUNCTION source. Directly supports cobalamin
      binding, cobalamin transport, and secreted localization. Abstract-only in cache.
- id: file:human/TCN2/TCN2-uniprot.txt
  title: UniProtKB P20062 (TCO2_HUMAN) Transcobalamin-2
  findings:
  - statement: UniProt describes transcobalamin-2 as the primary vitamin B12-binding and
      transport protein that delivers cobalamin to cells, is secreted, and interacts with
      CD320 via its LDL-receptor class A domains; loss of function causes transcobalamin
      II deficiency (TCN2D).
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record for P20062; supports secreted localization, function,
      CD320 interaction, and disease.
- id: Reactome:R-HSA-3000074
  title: TCN2 binds RCbl in the circulation
  findings: []
- id: Reactome:R-HSA-3000112
  title: CD320-mediated TCN2:RCbl uptake and delivery to lysosome
  findings: []
- id: Reactome:R-HSA-3000122
  title: CD320 binds extracellular TCN2:RCbl
  findings: []
- id: Reactome:R-HSA-3000263
  title: TCN2:RCbl is degraded to release RCbl
  findings: []
- id: Reactome:R-HSA-3299657
  title: Defective TCII does not bind Cbl in the circulation
  findings: []
- id: Reactome:R-HSA-3325546
  title: Defective CD320 does not transport extracellular TCII:Cbl to endosome
  findings: []
- id: Reactome:R-HSA-9758890
  title: Transport of RCbl within the body
  findings: []
- id: Reactome:R-HSA-9759202
  title: LRP2-mediated TCN2:RCbl uptake and delivery to lysosome
  findings: []
- id: Reactome:R-HSA-9759209
  title: LRP2 binds extracellular TCN2:RCbl
  findings: []

TCN2

Gene Description

Existing Annotations Review

Core Functions

Binds vitamin B12 (cobalamin) with 1:1 stoichiometry as the primary plasma cobalamin-binding protein, sequestering a single cobalamin molecule at the interface of its two structural domains.

Acts as the cargo-carrying ligand recognized by the cell-surface uptake receptor CD320 (TCblR), enabling receptor-mediated endocytosis of the transcobalamin-cobalamin complex and thereby delivery of vitamin B12 into cells.

As a secreted plasma protein, transports newly absorbed cobalamin from the circulation to peripheral cells throughout the body, the physiologically essential route supplying vitamin B12 to tissues.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

TCN2 (Transcobalamin-2 / Transcobalamin II) review notes

Core biology (verified)

Evidence from cached publications

GOA annotations (29 GOA rows → 27 stub entries; grouped)

Core function summary

Disease

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