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.
| 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. |
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Download this section (compressed HTML)Q: 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?
Q: Does apo-transcobalamin-2 have a distinct physiological function or receptor engagement compared with holo-transcobalamin-2?
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.
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