CD320

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that CD320 acts at the plasma membrane. This is correct and central to its function: CD320 is a single-pass type I cell-surface receptor that binds and internalizes the TC-Cbl complex from the extracellular space. Reason: Directly supported by experimental subcellular-location data and by the biology of the receptor. The plasma membrane is the site where CD320 captures circulating holo-transcobalamin. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location keyword mapping to plasma membrane. Consistent with the experimentally established cell-membrane localization of CD320. Reason: Redundant with, but consistent with, the experimental plasma membrane annotations (PMID:10727470, PMID:18779389). UniProt annotates "Cell membrane; Single-pass type I membrane protein". Supporting Evidence: file:human/CD320/CD320-uniprot.txt SUBCELLULAR LOCATION: Cell membrane
GO:0016020 membrane	IEA GO_REF:0000117	MODIFY	Summary: ARBA electronic annotation to the generic parent term "membrane". True but far less informative than the plasma membrane annotations. Reason: CD320 is a single-pass membrane protein, so "membrane" is not wrong, but the more specific and better-supported term is plasma membrane. Recommend replacing with the specific location. Proposed replacements: plasma membrane Supporting Evidence: file:human/CD320/CD320-uniprot.txt Single-pass
GO:0016192 vesicle-mediated transport	IEA GO_REF:0000117	MODIFY	Summary: ARBA electronic annotation to vesicle-mediated transport. CD320 internalizes its ligand by receptor-mediated endocytosis, which is a form of vesicle-mediated transport, so this is correct but general. Reason: The specific mechanism is receptor-mediated endocytosis of the TC-Cbl complex; recommend the more precise child term rather than the broad parent. Proposed replacements: receptor-mediated endocytosis 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:0005515 protein binding	IPI PMID:27411955 Structural basis of transcobalamin recognition by human CD32...	MARK AS OVER ANNOTATED	Summary: IntAct IPI capturing the physical interaction of CD320 with its physiological ligand transcobalamin (TCN2, P20062), shown by crystallography and biochemistry. "protein binding" is uninformative on its own; the informative molecular function is captured by cargo receptor activity (GO:0038024) and cobalamin binding (GO:0031419) in core_functions. Reason: The interaction is real and important (CD320-TCN2), but the bare "protein binding" term does not convey the receptor function. The specific cargo-receptor/cobalamin role is captured elsewhere; per curation guidelines the generic term is retained but flagged rather than used as a core function. Supporting Evidence: PMID:27411955 Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin file:human/CD320/CD320-uniprot.txt Interacts (via LDL-receptor class A domains) with TCN2
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	MARK AS OVER ANNOTATED	Summary: IntAct IPI from a large-scale human immune surface-receptor interactome screen, recording the CD320-JAML (AMICA1, Q86YT9) interaction; in that study CD320 contributed to natural killer cell activation. This is a secondary immune interaction distinct from the core B12-receptor function. Reason: A genuine physical interaction from a systematic screen, but "protein binding" is uninformative and this immune adhesion/costimulation role is peripheral to the core cobalamin-uptake function. Retained but flagged rather than treated as core. Supporting Evidence: PMID:35922511 the adhesion proteins CHL1 and CD320 (along with CD58 as previously described31) facilitating natural killer (NK) cell activation
GO:0015889 cobalamin transport	TAS Reactome:R-HSA-9758890	ACCEPT	Summary: Reactome traceable-author-statement annotation placing CD320 in cobalamin transport (transport of cobalamins within the body). This is a core biological process for CD320: it delivers TC-bound cobalamin into cells. Reason: Well supported by experimental literature (PMID:18779389, PMID:20524213) and by the Reactome pathway model of TC-Cbl uptake and distribution. Supporting Evidence: PMID:20524213 TCblR expressed on the plasma membrane binds transcobalamin (TC) saturated with Cbl (holo-TC) and mediates cellular uptake of Cbl
GO:0005886 plasma membrane	EXP PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f...	ACCEPT	Summary: Experimental plasma-membrane localization from the FDC-signaling-molecule 8D6 characterization (8D6 = CD320). CD320 is detected on follicular dendritic cells at the cell surface. Reason: Correct cell-surface localization; consistent with the receptor's function and with other experimental and IBA plasma-membrane annotations. Supporting Evidence: PMID:11418631 A novel FDC-signaling molecule 8D6 (FDC-SM-8D6) produced by FDC augments PC generation in the GC.
GO:0038024 cargo receptor activity	EXP PMID:15652495 The binding properties of the human receptor for the cellula...	ACCEPT	Summary: Experimental molecular-function annotation to cargo receptor activity. This is the core molecular function of CD320: it is the plasma-membrane receptor that binds the transcobalamin-cobalamin cargo and mediates its endocytic internalization. Reason: Directly supported: the receptor binds holo-TC and internalizes the TC-Cbl complex by endocytosis, the defining activity of an endocytic cargo receptor. Supporting Evidence: PMID:15652495 is mediated by a receptor PMID:15652495 internalizes the TC-Cbl by endocytosis
GO:0005509 calcium ion binding	IDA PMID:27411955 Structural basis of transcobalamin recognition by human CD32...	ACCEPT	Summary: Direct-assay calcium-ion binding from the crystal structure: each of the two LDLR-A domains of CD320 coordinates a central Ca2+ ion. Calcium is required for formation of the TC-CD320 complex and hence for ligand capture. Reason: Structurally demonstrated Ca2+ coordination in both LDLR-A domains (PDB:4ZRP/4ZRQ); UniProt annotates twelve Ca2+-binding residues across the two domains. This is a genuine structural molecular function underpinning ligand binding, though secondary to the cargo-receptor function. Supporting Evidence: PMID:27411955 Both LDLR-A domains contain central Ca2+ ions bound by four conserved acidic residues and two backbone carbonyls in an octahedral coordination.
GO:0005886 plasma membrane	IDA PMID:10727470 Identification of a human follicular dendritic cell molecule...	ACCEPT	Summary: Direct-assay plasma-membrane localization from the original 8D6/CD320 identification: the 8D6 antigen (CD320) is expressed abundantly on the surface of follicular dendritic cells. Reason: Correct and well supported cell-surface localization consistent with the receptor function. Supporting Evidence: PMID:10727470 The 8D6 Ag is a novel protein of 282 amino acids that is expressed abundantly on FDCs.
GO:0015889 cobalamin transport	IMP PMID:18779389 The protein and the gene encoding the receptor for the cellu...	ACCEPT	Summary: Cobalamin transport based on characterization of the purified receptor protein and its gene: TCblR/CD320 on the plasma membrane binds holo-TC and internalizes the complex by endocytosis, mediating cellular cobalamin uptake. Core biological process. Reason: Direct experimental basis for CD320's role in cobalamin transport; the receptor was purified and shown to bind and internalize TC-Cbl. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0030890 positive regulation of B cell proliferation	IMP PMID:10727470 Identification of a human follicular dendritic cell molecule...	KEEP AS NON CORE	Summary: Based on the original 8D6/CD320 characterization on follicular dendritic cells: CD320 (8D6 antigen) costimulates growth of germinal-center B cells, and blocking mAb 8D6 inhibits their proliferation. This is a genuine but tissue/context-specific immune role predating the identification of the B12-receptor function. Reason: Experimentally supported (IMP with blocking antibody), so retained; but this immune costimulatory activity is peripheral to CD320's universal core function as the transcobalamin/cobalamin-uptake receptor and is plausibly downstream of proliferation-coupled B12 supply. Marked non-core rather than removed, deferring to the experimental curation. Supporting Evidence: PMID:10727470 Monolayers of COS cells transiently transfected with the 8D6 Ag cDNA stimulate B cell growth.
GO:0031296 B cell costimulation	IMP PMID:10727470 Identification of a human follicular dendritic cell molecule...	KEEP AS NON CORE	Summary: CD320 (8D6 antigen) on follicular dendritic cells provides a costimulatory signal for germinal-center B-cell growth and differentiation; blocking mAb 8D6 abolishes this costimulation. Genuine but context-specific immune role. Reason: Experimentally supported costimulation activity, retained; peripheral to the core cobalamin-uptake receptor function and specific to the FDC-B cell context. Supporting Evidence: PMID:10727470 The mAb 8D6 blocks the costimulatory function completely.
GO:0015889 cobalamin transport	IMP PMID:20524213 Positive newborn screen for methylmalonic aciduria identifie...	ACCEPT	Summary: Cobalamin transport supported by the first disease mutation: an in-frame p.E88del in CD320 decreases uptake of holo-TC in patient fibroblasts and causes methylmalonic aciduria; reinserting the codon restores receptor function. Core biological process. Reason: Genetic loss-of-function evidence (IMP) directly ties CD320 to cobalamin transport, the only physiologic route for TC-bound cobalamin into cells. Supporting Evidence: PMID:20524213 The only route for physiologic transport of TC-bound Cbl into cells is via TCblR. PMID:20524213 Inserting the codon by site-directed mutagenesis fully restored TCblR function.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MODIFY	Summary: High-throughput mass-spectrometry detection of CD320 in the membrane proteome of an NK-like cell line. Supports membrane localization but at the generic "membrane" level. Reason: Correct that CD320 is membrane-associated, but this proteomic dataset does not distinguish membrane compartments; the specific and better-supported term is plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3325546	ACCEPT	Summary: Reactome TAS plasma-membrane annotation from the model of defective CD320 failing to transport TCII:Cbl to the endosome. Consistent with the receptor's cell-surface location. Reason: Correct cell-surface localization, corroborated by experimental data. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000112	ACCEPT	Summary: Reactome TAS plasma-membrane annotation from the CD320-mediated TCN2:RCbl uptake and lysosomal delivery model, in which CD320 recycles to the plasma membrane after internalization. Reason: Correct cell-surface localization; the receptor cycles between the plasma membrane and endosomes during ligand uptake. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3000122	ACCEPT	Summary: Reactome TAS plasma-membrane annotation from the "CD320 binds extracellular TCN2:RCbl" reaction. Consistent with the receptor capturing its ligand at the cell surface. Reason: Correct cell-surface localization; site of ligand capture. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0005886 plasma membrane	IDA PMID:18779389 The protein and the gene encoding the receptor for the cellu...	ACCEPT	Summary: MGI-assigned direct-assay plasma-membrane localization from characterization of the purified receptor. The receptor is a plasma-membrane protein that binds and internalizes TC-Cbl. Reason: Directly supported cell-surface localization consistent with all other localization evidence. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis.
GO:0031419 cobalamin binding	IDA PMID:18779389 The protein and the gene encoding the receptor for the cellu...	ACCEPT	Summary: Direct-assay cobalamin binding: CD320 binds cobalamin in the form of the transcobalamin-cobalamin complex (holo-TC), the ligand it captures at the cell surface. Core molecular function alongside cargo receptor activity. Reason: The purified receptor binds holo-TC (TC saturated with Cbl); recognition of the cobalamin-loaded ligand is central to its function. LDLR-family; binds TC-Cbl with high affinity. Supporting Evidence: PMID:18779389 The transcobalamin (TC, TCII) receptor (TCblR) on the plasma membrane binds TC- cobalamin (Cbl) and internalizes the complex by endocytosis. PMID:18779389 TCblR belongs to the low-density lipoprotein receptor family
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000054	MARK AS OVER ANNOTATED	Summary: LIFEdb annotation from imaging of an overexpressed GFP/epitope-tagged fusion protein. ER signal for a plasma-membrane receptor most likely reflects the biosynthetic/secretory pathway of an overexpressed membrane protein rather than a functional ER localization. Reason: CD320 is a single-pass plasma-membrane receptor; like all such proteins it transits the ER during biosynthesis, but its functional compartment is the cell surface (and endosomes during uptake). ER localization from a single high-throughput overexpressed-fusion assay is not a core function and is an over-annotation of the functional site. Supporting Evidence: file:human/CD320/CD320-uniprot.txt SUBCELLULAR LOCATION: Cell membrane

Gene Description

Existing Annotations Review

Core Functions

Cell-surface cargo/endocytic receptor that captures the transcobalamin-cobalamin complex (holo-TC) from plasma and mediates its uptake by receptor-mediated endocytosis, delivering vitamin B12 (cobalamin) into cells.

Internalization of the bound transcobalamin-cobalamin ligand from the plasma membrane via receptor-mediated endocytosis; ligand is released at endosomal low pH and the receptor recycles to the cell surface.

Recognition and binding of cobalamin in the form of the transcobalamin-cobalamin (holo-TC) complex, the ligand captured by CD320 at the cell surface.

References

📚 Additional Documentation

Notes

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