ABCD4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005778 peroxisomal membrane	IBA GO_REF:0000033	REMOVE	Summary: Phylogenetic (IBA) propagation of a peroxisomal-membrane location from the peroxisomal ABCD1-ABCD3 paralogs. ABCD4 is not peroxisomal; it resides in the ER and lysosomal membranes and lacks the N-terminal peroxisomal targeting signal. Reason: Direct experimental evidence shows ABCD4 localizes to the ER and lysosomal membrane, not peroxisomes, and the original peroxisomal assignment has been overturned (UniProt CAUTION note). This IBA is over-propagated from peroxisomal paralogs and is contradicted by the primary data. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P28288 ABCD3/PMP70, peroxisomal-membrane paralog; peroxisomal location does not transfer to lysosomal/ER ABCD4. UniProtKB:P33897 ABCD1/ALDP, peroxisomal-membrane paralog; peroxisomal location does not transfer to ABCD4. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein PMID:19010322 reticulum (ER), not to peroxisomes.
GO:0042626 ATPase-coupled transmembrane transporter activity	IBA GO_REF:0000033	MODIFY	Summary: General ABC-transporter molecular function (ATPase-coupled transmembrane transport) inferred phylogenetically. This is correct for ABCD4 in essence but is more general than the demonstrated cobalamin-specific activity. Reason: ABCD4 is an ATP-driven transmembrane transporter, so the parent term is not wrong, but experimental data define its substrate as cobalamin. Replace with the specific ABC-type vitamin B12 transporter activity that is directly supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008319914 Family-level ATPase-coupled transporter activity is true but too broad; ABCD4's substrate-specific vitamin B12 transporter activity is experimentally established. Proposed replacements: ABC-type vitamin B12 transporter activity Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0005324 long-chain fatty acid transmembrane transporter activity	IBA GO_REF:0000033	REMOVE	Summary: Long-chain fatty acid transporter activity propagated from the peroxisomal fatty-acyl-CoA transporters ABCD1-ABCD3. ABCD4's demonstrated substrate is cobalamin, not fatty acids. Reason: The substrate of ABCD4 has been experimentally established as cobalamin; there is no evidence it transports long-chain fatty acids. This IBA is an over-propagation from the peroxisomal ABCD paralogs and is biologically incorrect for ABCD4. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:P28288 ABCD3/PMP70 transports long-chain fatty acyl-CoA; ABCD4 diverged to a cobalamin substrate. UniProtKB:P33897 ABCD1/ALDP transports very-long-chain fatty acyl-CoA; substrate does not transfer to ABCD4. Supporting Evidence: PMID:33845046 the cobalamin inside liposomes is recognized by ABCD4 as substrate and stimulates the ATP hydrolysis of ABCD4
GO:0006635 fatty acid beta-oxidation	IBA GO_REF:0000033	REMOVE	Summary: Fatty acid beta-oxidation is the peroxisomal process served by ABCD1-ABCD3; propagated to ABCD4 phylogenetically. ABCD4 acts in lysosomal cobalamin export, not fatty acid catabolism. Reason: No evidence links ABCD4 to fatty acid beta-oxidation; its established role is in cobalamin transport/metabolism. This IBA is over-propagated from the peroxisomal fatty-acid-transporting paralogs. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:P28288 ABCD3/PMP70 feeds peroxisomal beta-oxidation; ABCD4 acts in lysosomal cobalamin export, not fatty acid catabolism. UniProtKB:P33897 ABCD1/ALDP feeds peroxisomal beta-oxidation; role does not transfer to ABCD4. Supporting Evidence: PMID:22922874 the ATPase activity of ABCD4 may
GO:0015910 long-chain fatty acid import into peroxisome	IBA GO_REF:0000033	REMOVE	Summary: Peroxisomal long-chain fatty acid import propagated from ABCD1-ABCD3. Both the process (fatty acid import) and the location (peroxisome) are incorrect for ABCD4. Reason: ABCD4 is not peroxisomal and does not transport fatty acids; it exports cobalamin across the lysosomal membrane. This IBA is doubly contradicted by the experimental localization and substrate data. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P28288 ABCD3/PMP70 imports fatty acids into peroxisomes; neither the substrate nor the peroxisomal compartment transfers to ABCD4. UniProtKB:P33897 ABCD1/ALDP imports VLCFA into peroxisomes; process and compartment do not transfer to lysosomal ABCD4. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein
GO:0042760 very long-chain fatty acid catabolic process	IBA GO_REF:0000033	REMOVE	Summary: Very-long-chain fatty acid catabolism, the peroxisomal role of ABCD1-ABCD3, propagated to ABCD4. Not supported for ABCD4, whose substrate is cobalamin. Reason: No evidence supports a role for ABCD4 in VLCFA catabolism; this IBA is over-propagated from the peroxisomal ABCD paralogs and is contradicted by the demonstrated cobalamin-transport function. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:P33897 ABCD1/ALDP supplies VLCFA for peroxisomal catabolism; role does not transfer to cobalamin-transporting ABCD4. UniProtKB:P28288 ABCD3/PMP70 acts in peroxisomal fatty acid catabolism; not transferable to ABCD4. Supporting Evidence: PMID:33845046 the cobalamin inside liposomes is recognized by ABCD4 as substrate and stimulates the ATP hydrolysis of ABCD4
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: ATP binding by the nucleotide-binding domain, inferred phylogenetically and consistent with the Walker A/B motifs and demonstrated ATPase-dependent transport. Reason: ABCD4 contains a canonical ABC nucleotide-binding domain (Walker A motif, residues 421-428) and its transport activity is ATP-hydrolysis-dependent (K427A Walker A mutant abolishes activity), so ATP binding is well supported. Supporting Evidence: PMID:33845046 ABCD4 (K427A) had lost transport activity in addition to ATPase activity
GO:0007031 peroxisome organization	IBA GO_REF:0000033	REMOVE	Summary: Peroxisome organization propagated from peroxisomal paralogs. ABCD4 is not a peroxisomal protein and has no established role in peroxisome biogenesis. Reason: ABCD4 localizes to ER/lysosome, not peroxisomes; there is no evidence it participates in peroxisome organization. This IBA is over-propagated from the peroxisomal ABCD subfamily. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P28288 ABCD3/PMP70 is a peroxisomal-membrane protein linked to peroxisome organization; not applicable to lysosomal/ER ABCD4. UniProtKB:P33897 ABCD1/ALDP is peroxisomal; peroxisome-organization role does not transfer to ABCD4. Supporting Evidence: PMID:19010322 reticulum (ER), not to peroxisomes.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based ATP binding from the ABC transporter ATP-binding domain signatures. Consistent with the experimentally supported nucleotide-binding domain. Reason: The InterPro domain signatures (ABC transporter-like ATP-binding domain) correctly identify the nucleotide-binding domain; ATP binding is supported by the Walker A motif and ATPase-dependent transport. Supporting Evidence: PMID:33845046 ABCD4 (K427A) had lost transport activity in addition to ATPase activity
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt Subcellular Location mapping to the lysosomal membrane, corroborated by multiple experimental studies. Reason: The lysosomal membrane is the functional location of ABCD4, established experimentally; the SubCell IEA is consistent with the direct evidence. Supporting Evidence: file:human/ABCD4/ABCD4-uniprot.txt Lysosome membrane {ECO PMID:22922874 in failure to release vitamin B12 from lysosomes, which mimics the cblF defect
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: Automated (multi-method) mapping to the ER membrane. ABCD4 is co-translationally inserted into the ER before LMBD1-dependent translocation to lysosomes, so ER membrane is a genuine (biosynthetic-intermediate) location. Reason: Experimental studies show endogenous ABCD4 resides in both the ER and lysosomal membranes, the ER being the site of synthesis/insertion prior to LMBD1-mediated lysosomal targeting. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein PMID:19010322 P70R-HA was localized to the endoplasmic
GO:0015420 ABC-type vitamin B12 transporter activity	IEA GO_REF:0000003	ACCEPT	Summary: EC 7.6.2.8 (ABC-type vitamin B12 transporter) mapped to the specific GO molecular function. This matches the experimentally demonstrated cobalamin transport activity of ABCD4. Reason: This is the core molecular function of ABCD4, independently supported by direct in vitro transport assays. The EC-to-GO mapping is correct. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Generic membrane localization from InterPro transmembrane-domain signatures. Correct but uninformative given the specific lysosomal/ER membrane annotations. Reason: ABCD4 is a multi-pass membrane protein, so "membrane" is not wrong, but it is subsumed by the more specific lysosomal membrane and ER membrane annotations and adds no information. Supporting Evidence: file:human/ABCD4/ABCD4-uniprot.txt Lysosome membrane {ECO
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: ATP hydrolysis activity from InterPro ABC ATP-binding domain signatures. Directly supported by ATPase assays on purified, reconstituted ABCD4. Reason: Reconstituted ABCD4 exhibits ATPase activity that is stimulated by luminal cobalamin and abolished by the Walker A K427A mutation, confirming ATP hydrolysis as an intrinsic activity coupled to transport. Supporting Evidence: PMID:33845046 the cobalamin inside liposomes is recognized by ABCD4 as substrate and stimulates the ATP hydrolysis of ABCD4
GO:0055085 transmembrane transport	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Generic transmembrane transport from InterPro. Correct but far more general than the specific cobalamin transport process ABCD4 mediates. Reason: ABCD4 does mediate transmembrane transport, but this is a high-level parent of the specific and better-supported cobalamin transport annotation; it is uninformative on its own. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0140359 ABC-type transporter activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: General ABC-type transporter activity from InterPro ABC signatures. True but more general than the specific ABC-type vitamin B12 transporter activity. Reason: ABCD4 is an ABC-type transporter, so the term is not wrong, but the substrate-specific GO:0015420 (ABC-type vitamin B12 transporter activity) is experimentally established and preferred; this parent term over-annotates. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0005515 protein binding	IPI PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas...	MARK AS OVER ANNOTATED	Summary: IPI capturing the ABCD4-LMBD1 (LMBRD1, Q9NUN5) interaction. This is a functionally important interaction (LMBD1 escorts ABCD4 from the ER to the lysosome), but the bare "protein binding" term is uninformative. Reason: The underlying interaction with LMBD1 is real and biologically central, but "protein binding" conveys no specific molecular function. Per curation guidelines, such bare GO:0005515 IPIs should not be treated as core; the functional partnership is captured in the description and core functions. Supporting Evidence: PMID:27456980 this translocation depends on the lysosomal targeting ability of
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" IPI from a proteome-scale interactome screen (BioPlex) capturing the FAM234B (A2RU67) interaction. Reason: High-throughput interactome hit with an uninformative term; no specific molecular function is defined and the physiological relevance of the FAM234B hit is unestablished. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:28572511 Clinical or ATPase domain mutations in ABCD4 disrupt the int...	MARK AS OVER ANNOTATED	Summary: IPI capturing the ABCD4-LMBD1 interaction demonstrated by a live-cell FRET assay. Functionally important but the bare term is uninformative. Reason: The ABCD4-LMBD1 interaction is real and central to ABCD4 targeting and function, but "protein binding" is non-informative; the partnership is captured elsewhere in the review. Supporting Evidence: PMID:28572511 we demonstrated selective
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" IPI from a proteome-scale interactome screen (BioPlex 3.0) capturing the FAM234B (A2RU67) interaction. Reason: High-throughput interactome hit with an uninformative term; no specific molecular function is defined. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0042802 identical protein binding	IPI PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas...	KEEP AS NON CORE	Summary: Self-interaction (homodimerization) of ABCD4, consistent with its function as a half-size ABC transporter that operates as a homodimer. Reason: ABCD4 is a half-transporter that assembles into a homodimer to form the functional unit, so identical protein binding is genuine and biologically meaningful, but it is a structural/assembly property rather than the core catalytic function. Supporting Evidence: PMID:27456980 consistent in mass with dimeric ABCD4
GO:0042802 identical protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Self-interaction of ABCD4 detected in a multimodal cell-mapping/interactome study, consistent with homodimer assembly. Reason: Supports the homodimeric assembly of ABCD4; genuine but a structural property rather than the core transport function. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics.
GO:0015889 cobalamin transport	TAS Reactome:R-HSA-9758881	ACCEPT	Summary: Reactome-asserted involvement in cobalamin transport (dietary cobalamin uptake pathway). This is the core biological process of ABCD4. Reason: Cobalamin transport across the lysosomal membrane is the established core role of ABCD4, independently supported by experimental transport and disease data. Supporting Evidence: PMID:33845046 ABCD4 plays a key role in the transport of cobalamin from the lysosomal lumen to the cytosol
GO:0015889 cobalamin transport	TAS Reactome:R-HSA-9758890	ACCEPT	Summary: Reactome-asserted involvement in cobalamin transport (transport of RCbl within the body). Core biological process of ABCD4. Reason: Duplicate assertion of the core cobalamin-transport role from a related Reactome pathway; well supported by experimental and clinical evidence. Supporting Evidence: PMID:33845046 ABCD4 plays a key role in the transport of cobalamin from the lysosomal lumen to the cytosol
GO:0015420 ABC-type vitamin B12 transporter activity	EXP PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: Direct in vitro demonstration that purified, reconstituted ABCD4 transports cobalamin across liposomal membranes in an ATP-dependent manner. This is the definitive core molecular function. Reason: The strongest evidence for ABCD4's function - reconstituted ABCD4 transports cobalamin (Km 426 uM), the activity is ATPase-dependent, and the Walker A K427A mutant abolishes both ATPase and transport. Defines the exact core MF. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0005765 lysosomal membrane	EXP PMID:22922874 Mutations in ABCD4 cause a new inborn error of vitamin B12 m...	ACCEPT	Summary: Experimental demonstration that ABCD4 colocalizes with the lysosomal markers LAMP1 and LMBD1, establishing lysosomal membrane localization. Reason: Directly supported experimental localization to the lysosomal membrane, the functional site of ABCD4's cobalamin-export activity. Supporting Evidence: PMID:22922874 in failure to release vitamin B12 from lysosomes, which mimics the cblF defect
GO:0005765 lysosomal membrane	EXP PMID:25535791 Purification and interaction analyses of two human lysosomal...	ACCEPT	Summary: Lysosomal vitamin B12 transporter localization from the ABCD4/LMBD1 purification and interaction study. Reason: Consistent, well-supported lysosomal membrane localization; ABCD4 is one of the two lysosomal membrane B12 transporters characterized in this work. Supporting Evidence: PMID:25535791 Mutations in human LMBRD1 and ABCD4 prevent lysosomal export of vitamin B(12) to
GO:0005765 lysosomal membrane	EXP PMID:28572511 Clinical or ATPase domain mutations in ABCD4 disrupt the int...	ACCEPT	Summary: Lysosomal targeting of ABCD4 (dependent on LMBD1 co-expression) shown by live-cell assays. Reason: Experimental support for lysosomal membrane localization; the study also shows this localization depends on interaction with LMBD1. Supporting Evidence: PMID:28572511 targeting depends on co-expression of, and interaction with, LMBD1. These data
GO:0005765 lysosomal membrane	IDA PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: ABCD4 is active (transports cobalamin) at the lysosomal membrane, its physiological site of action. Reason: The lysosomal membrane is where ABCD4 performs its cobalamin-export function; is_active_in is appropriate given the demonstrated transport activity and lysosomal localization. Supporting Evidence: PMID:33845046 ABCD4 is located on lysosomal membrane
GO:0009235 cobalamin metabolic process	IDA PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: ABCD4 participates in cobalamin metabolism by exporting lysosomal cobalamin to the cytosol for cofactor synthesis. Reason: By delivering cobalamin to the cytosol for conversion to methylcobalamin and adenosylcobalamin, ABCD4 is a core component of intracellular cobalamin metabolism; directly supported. Supporting Evidence: PMID:33845046 cobalamin is released into the cytosol and converted into two active cofactors: methylcobalamin and adenosylcobalamin
GO:0015420 ABC-type vitamin B12 transporter activity	IDA PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: Direct-assay support (IDA) for the ABC-type vitamin B12 transporter activity of ABCD4. Core molecular function. Reason: Same definitive in vitro transport evidence; the exact GOA MF term for ABCD4's core function. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0005765 lysosomal membrane	IDA PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: Direct-assay lysosomal membrane localization of ABCD4. Reason: Consistent with all other experimental evidence for lysosomal membrane localization. Supporting Evidence: PMID:33845046 ABCD4 is located on lysosomal membrane
GO:0005515 protein binding	IPI PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	MARK AS OVER ANNOTATED	Summary: IPI capturing the ABCD4-LMBD1 (Q9NUN5) interaction from the in vitro pull-down/crosslinking analyses. Functionally central but the bare term is uninformative. Reason: The purified ABCD4-LMBD1 interaction (1:1 stoichiometry) is genuine and biologically important, but "protein binding" is a non-informative term; the partnership is captured in the description and core functions. Supporting Evidence: PMID:33845046 purified ABCD4 and LMBD1 interact each other with a 1:1 stoichiometry
GO:0015420 ABC-type vitamin B12 transporter activity	IMP PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: Mutant-phenotype support (IMP) for the ABC-type vitamin B12 transporter activity - disease and engineered mutations abolish cobalamin transport. Reason: Loss-of-function mutations (e.g. Walker A K427A, clinical Y319C) abolish cobalamin transport, providing mutant-phenotype evidence for this core molecular function. Supporting Evidence: PMID:33845046 ABCD4 (K427A) had lost transport activity in addition to ATPase activity
GO:0015889 cobalamin transport	IMP PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro...	ACCEPT	Summary: Mutant-phenotype support for ABCD4's role in cobalamin transport. Core biological process. Reason: Mutations that impair ABCD4 abolish cobalamin transport across the lysosomal membrane, directly implicating ABCD4 in this process. Supporting Evidence: PMID:33845046 ABCD4 plays a key role in the transport of cobalamin from the lysosomal lumen to the cytosol
GO:0005765 lysosomal membrane	IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas...	ACCEPT	Summary: Direct-assay lysosomal membrane localization; ABCD4 localizes to lysosomes upon LMBD1-mediated translocation from the ER. Reason: Well-supported experimental localization; the study establishes that lysosomal localization is achieved via LMBD1-dependent translocation. Supporting Evidence: PMID:27456980 this translocation depends on the lysosomal targeting ability of
GO:0005789 endoplasmic reticulum membrane	IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas...	ACCEPT	Summary: Direct-assay ER membrane localization; ABCD4 is an ER-resident protein before LMBD1-dependent lysosomal targeting. Reason: Experimentally demonstrated ER localization (biosynthetic-intermediate site); endogenous ABCD4 distributes between ER and lysosome, with LMBD1 controlling the lysosomal fraction. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein
GO:0005515 protein binding	IPI PMID:25535791 Purification and interaction analyses of two human lysosomal...	MARK AS OVER ANNOTATED	Summary: IPI capturing the ABCD4 interactions with LMBD1 (Q9NUN5) and MMACHC (Q9Y4U1) from SPR/biophysical analyses. Both are functionally central (lysosomal cobalamin-to-cytosol trafficking complex), but the bare term is uninformative. Reason: The ABCD4-LMBD1 and ABCD4-MMACHC interactions (both low nanomolar affinity) are genuine and important for vectorial cobalamin delivery, but "protein binding" is non-informative; the interactions are captured in the description and core functions. Supporting Evidence: PMID:25535791 LMBD1 and ABCD4 interact with low PMID:25535791 MMACHC also interacts with LMBD1 and ABCD4 with low nanomolar affinity.
GO:0005777 peroxisome	IDA NOT PMID:19010322 70-kDa peroxisomal membrane protein related protein (P70R/AB...	ACCEPT	Summary: NOT annotation - ABCD4 does NOT localize to peroxisomes. This study showed P70R/ABCD4 localizes to the ER, not peroxisomes. Reason: Correct negative annotation directly supported by the primary data overturning the original peroxisomal assignment. Supporting Evidence: PMID:19010322 reticulum (ER), not to peroxisomes.
GO:0005777 peroxisome	IDA NOT PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas...	ACCEPT	Summary: NOT annotation - ABCD4 does NOT localize to peroxisomes; it is an ER/lysosomal protein. Reason: Correct negative annotation; the study explicitly shows ABCD4 is not a peroxisomal protein. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein
GO:0005777 peroxisome	IDA PMID:14533738 Targeting of the human adrenoleukodystrophy protein to the p...	REMOVE	Summary: Positive peroxisome localization reflecting the superseded early view of ABCD4 as a peroxisomal half-transporter. This paper is principally about ALDP (ABCD1) peroxisomal targeting and uses a PMP69/ABCD4 fragment fused to reporter. Reason: The peroxisomal localization of full-length ABCD4 has been overturned by subsequent direct evidence (ER/lysosome; NOT\|peroxisome IDAs; UniProt CAUTION). This positive peroxisome annotation is contradicted by the current consensus and should be removed in favor of the negated peroxisome and lysosomal annotations. Supporting Evidence: PMID:27456980 ABCD4 was not a peroxisomal protein, but rather, an ER protein PMID:19010322 reticulum (ER), not to peroxisomes.
GO:0005777 peroxisome	IDA PMID:9302272 Identification of a fourth half ABC transporter in the human...	REMOVE	Summary: Original identification of ABCD4 (P70R) as a fourth half ABC transporter in the human peroxisomal membrane - the initial, now-superseded peroxisomal assignment. Reason: This early peroxisomal-membrane localization has been overturned; ABCD4 is an ER/lysosomal protein lacking a peroxisomal targeting signal (UniProt CAUTION; PMID:19010322, PMID:27456980). The positive peroxisome annotation is contradicted by the subsequent NOT\|peroxisome experimental data. Supporting Evidence: PMID:19010322 reticulum (ER), not to peroxisomes.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-5683325	ACCEPT	Summary: Reactome-asserted lysosomal membrane localization (defective-transport event). Consistent with all experimental localization data. Reason: Correct lysosomal membrane localization, agreeing with the direct experimental evidence. Supporting Evidence: PMID:22922874 in failure to release vitamin B12 from lysosomes, which mimics the cblF defect
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-5223313	ACCEPT	Summary: Reactome-asserted lysosomal membrane localization (RCbl transport in gut mucosal cells). Consistent with experimental data. Reason: Correct lysosomal membrane localization. Supporting Evidence: PMID:33845046 ABCD4 is located on lysosomal membrane
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9759206	ACCEPT	Summary: Reactome-asserted lysosomal membrane localization (ABCD4-LMBRD1 transports RCbl from lysosomal lumen to cytosol). Consistent with experimental data. Reason: Correct lysosomal membrane localization, matching the functional ABCD4-LMBRD1 export event. Supporting Evidence: PMID:33845046 ABCD4 is located on lysosomal membrane
GO:0009235 cobalamin metabolic process	IMP PMID:22922874 Mutations in ABCD4 cause a new inborn error of vitamin B12 m...	ACCEPT	Summary: Mutant-phenotype support for ABCD4's role in cobalamin metabolism - mutations cause a new inborn error of vitamin B12 metabolism (cblJ). Reason: ABCD4 mutations cause failure to release cobalamin from lysosomes and impaired cofactor synthesis, directly implicating ABCD4 in cobalamin metabolism. Supporting Evidence: PMID:22922874 the ATPase activity of ABCD4 may
GO:0005524 ATP binding	NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC...	ACCEPT	Summary: Author statement of ATP binding based on the ABC-half-transporter sequence identification. Consistent with the experimentally confirmed nucleotide-binding domain. Reason: ATP binding is supported by the canonical ABC nucleotide-binding domain and by subsequent ATPase-dependent transport assays; the NAS assertion is correct. Supporting Evidence: PMID:9266848 ABC-half-transporters require a partner
GO:0016020 membrane	NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC...	MARK AS OVER ANNOTATED	Summary: Author statement of membrane localization from the original cloning paper. Generic; subsumed by the specific lysosomal/ER membrane annotations. Reason: ABCD4 is a membrane protein, so this is not wrong, but the term is uninformative relative to the specific lysosomal membrane and ER membrane annotations. Supporting Evidence: file:human/ABCD4/ABCD4-uniprot.txt Lysosome membrane {ECO
GO:0042626 ATPase-coupled transmembrane transporter activity	NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC...	MODIFY	Summary: Author-stated ABC (ATPase-coupled) transporter activity from the original cloning paper. Correct at the family level but more general than the demonstrated cobalamin-specific activity. Reason: The essence (ATP-driven transmembrane transport) is correct, but the specific ABC-type vitamin B12 transporter activity is now experimentally established and should be used. Proposed replacements: ABC-type vitamin B12 transporter activity Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity
GO:0043190 ATP-binding cassette (ABC) transporter complex	NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC...	ACCEPT	Summary: Author statement that ABCD4 is part of an ABC transporter complex. ABCD4 is a half-transporter that functions as a homodimer (and associates with LMBD1), so it is part of an ABC transporter complex. Reason: As a half-size ABC transporter, ABCD4 assembles into a homodimeric functional complex, consistent with this cellular-component annotation. Supporting Evidence: PMID:9266848 ABC-half-transporter to constitute a functional complex, either as a homodimer
GO:0055085 transmembrane transport	NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC...	MARK AS OVER ANNOTATED	Summary: Author statement of transmembrane transport involvement. Correct but far more general than the specific cobalamin transport process. Reason: ABCD4 mediates transmembrane transport, but this high-level parent is subsumed by the specific and better-supported cobalamin transport annotation. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity

📄 View Raw YAML

id: O14678
gene_symbol: ABCD4
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ABCD4 (cblJ complementation group; formerly PMP69/P70R/PXMP1-L) is a half-size
  ATP-binding cassette (ABC) transporter of subfamily D that exports cobalamin (vitamin
  B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner. Unlike its
  peroxisomal paralogs ABCD1-ABCD3, ABCD4 lacks its own organelle-targeting signal; it
  is co-translationally inserted into the endoplasmic reticulum membrane and requires
  the lysosomal escort protein LMBD1 (LMBRD1) to translocate to and localize at the
  lysosomal membrane, where it functions as a homodimer. After transcobalamin-bound
  cobalamin is endocytosed and degraded in the lysosome, ABCD4 (in concert with LMBD1
  and the cytosolic processing protein MMACHC) delivers free cobalamin to the cytosol
  for conversion to methylcobalamin and adenosylcobalamin, the cofactors of methionine
  synthase and methylmalonyl-CoA mutase. Loss-of-function mutations cause methylmalonic
  aciduria and homocystinuria type cblJ (MAHCJ), characterized by failure to release
  cobalamin from lysosomes and reduced levels of both cobalamin cofactors.
existing_annotations:
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) propagation of a peroxisomal-membrane location from the
      peroxisomal ABCD1-ABCD3 paralogs. ABCD4 is not peroxisomal; it resides in the ER
      and lysosomal membranes and lacks the N-terminal peroxisomal targeting signal.
    action: REMOVE
    reason: Direct experimental evidence shows ABCD4 localizes to the ER and lysosomal
      membrane, not peroxisomes, and the original peroxisomal assignment has been
      overturned (UniProt CAUTION note). This IBA is over-propagated from peroxisomal
      paralogs and is contradicted by the primary data.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70, peroxisomal-membrane paralog; peroxisomal location does
          not transfer to lysosomal/ER ABCD4.
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP, peroxisomal-membrane paralog; peroxisomal location does not
          transfer to ABCD4.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
    - reference_id: PMID:19010322
      supporting_text: "reticulum (ER), not to peroxisomes."
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: General ABC-transporter molecular function (ATPase-coupled transmembrane
      transport) inferred phylogenetically. This is correct for ABCD4 in essence but
      is more general than the demonstrated cobalamin-specific activity.
    action: MODIFY
    reason: ABCD4 is an ATP-driven transmembrane transporter, so the parent term is not
      wrong, but experimental data define its substrate as cobalamin. Replace with the
      specific ABC-type vitamin B12 transporter activity that is directly supported.
    proposed_replacement_terms:
    - id: GO:0015420
      label: ABC-type vitamin B12 transporter activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN008319914
        comment: Family-level ATPase-coupled transporter activity is true but too broad;
          ABCD4's substrate-specific vitamin B12 transporter activity is experimentally
          established.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Long-chain fatty acid transporter activity propagated from the peroxisomal
      fatty-acyl-CoA transporters ABCD1-ABCD3. ABCD4's demonstrated substrate is
      cobalamin, not fatty acids.
    action: REMOVE
    reason: The substrate of ABCD4 has been experimentally established as cobalamin;
      there is no evidence it transports long-chain fatty acids. This IBA is an
      over-propagation from the peroxisomal ABCD paralogs and is biologically incorrect
      for ABCD4.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70 transports long-chain fatty acyl-CoA; ABCD4 diverged to a
          cobalamin substrate.
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP transports very-long-chain fatty acyl-CoA; substrate does not
          transfer to ABCD4.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: the cobalamin inside liposomes is recognized by ABCD4 as substrate
        and stimulates the ATP hydrolysis of ABCD4
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Fatty acid beta-oxidation is the peroxisomal process served by ABCD1-ABCD3;
      propagated to ABCD4 phylogenetically. ABCD4 acts in lysosomal cobalamin export,
      not fatty acid catabolism.
    action: REMOVE
    reason: No evidence links ABCD4 to fatty acid beta-oxidation; its established role
      is in cobalamin transport/metabolism. This IBA is over-propagated from the
      peroxisomal fatty-acid-transporting paralogs.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70 feeds peroxisomal beta-oxidation; ABCD4 acts in lysosomal
          cobalamin export, not fatty acid catabolism.
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP feeds peroxisomal beta-oxidation; role does not transfer to
          ABCD4.
    supported_by:
    - reference_id: PMID:22922874
      supporting_text: "the ATPase activity of ABCD4 may"
- term:
    id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Peroxisomal long-chain fatty acid import propagated from ABCD1-ABCD3. Both
      the process (fatty acid import) and the location (peroxisome) are incorrect for
      ABCD4.
    action: REMOVE
    reason: ABCD4 is not peroxisomal and does not transport fatty acids; it exports
      cobalamin across the lysosomal membrane. This IBA is doubly contradicted by the
      experimental localization and substrate data.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - FUNCTIONAL_DIVERGENCE
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70 imports fatty acids into peroxisomes; neither the substrate
          nor the peroxisomal compartment transfers to ABCD4.
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP imports VLCFA into peroxisomes; process and compartment do
          not transfer to lysosomal ABCD4.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
- term:
    id: GO:0042760
    label: very long-chain fatty acid catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Very-long-chain fatty acid catabolism, the peroxisomal role of ABCD1-ABCD3,
      propagated to ABCD4. Not supported for ABCD4, whose substrate is cobalamin.
    action: REMOVE
    reason: No evidence supports a role for ABCD4 in VLCFA catabolism; this IBA is
      over-propagated from the peroxisomal ABCD paralogs and is contradicted by the
      demonstrated cobalamin-transport function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP supplies VLCFA for peroxisomal catabolism; role does not
          transfer to cobalamin-transporting ABCD4.
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70 acts in peroxisomal fatty acid catabolism; not transferable
          to ABCD4.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: the cobalamin inside liposomes is recognized by ABCD4 as substrate
        and stimulates the ATP hydrolysis of ABCD4
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ATP binding by the nucleotide-binding domain, inferred phylogenetically and
      consistent with the Walker A/B motifs and demonstrated ATPase-dependent transport.
    action: ACCEPT
    reason: ABCD4 contains a canonical ABC nucleotide-binding domain (Walker A motif,
      residues 421-428) and its transport activity is ATP-hydrolysis-dependent (K427A
      Walker A mutant abolishes activity), so ATP binding is well supported.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 (K427A) had lost transport activity in addition to ATPase activity
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Peroxisome organization propagated from peroxisomal paralogs. ABCD4 is not
      a peroxisomal protein and has no established role in peroxisome biogenesis.
    action: REMOVE
    reason: ABCD4 localizes to ER/lysosome, not peroxisomes; there is no evidence it
      participates in peroxisome organization. This IBA is over-propagated from the
      peroxisomal ABCD subfamily.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:P28288
        comment: ABCD3/PMP70 is a peroxisomal-membrane protein linked to peroxisome
          organization; not applicable to lysosomal/ER ABCD4.
      - source_id: UniProtKB:P33897
        comment: ABCD1/ALDP is peroxisomal; peroxisome-organization role does not transfer
          to ABCD4.
    supported_by:
    - reference_id: PMID:19010322
      supporting_text: "reticulum (ER), not to peroxisomes."
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based ATP binding from the ABC transporter ATP-binding domain
      signatures. Consistent with the experimentally supported nucleotide-binding
      domain.
    action: ACCEPT
    reason: The InterPro domain signatures (ABC transporter-like ATP-binding domain)
      correctly identify the nucleotide-binding domain; ATP binding is supported by the
      Walker A motif and ATPase-dependent transport.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 (K427A) had lost transport activity in addition to ATPase activity
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt Subcellular Location mapping to the lysosomal membrane, corroborated
      by multiple experimental studies.
    action: ACCEPT
    reason: The lysosomal membrane is the functional location of ABCD4, established
      experimentally; the SubCell IEA is consistent with the direct evidence.
    supported_by:
    - reference_id: file:human/ABCD4/ABCD4-uniprot.txt
      supporting_text: Lysosome membrane {ECO
    - reference_id: PMID:22922874
      supporting_text: "in failure to release vitamin B12 from lysosomes, which mimics the cblF defect"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated (multi-method) mapping to the ER membrane. ABCD4 is co-translationally
      inserted into the ER before LMBD1-dependent translocation to lysosomes, so ER
      membrane is a genuine (biosynthetic-intermediate) location.
    action: ACCEPT
    reason: Experimental studies show endogenous ABCD4 resides in both the ER and
      lysosomal membranes, the ER being the site of synthesis/insertion prior to
      LMBD1-mediated lysosomal targeting.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
    - reference_id: PMID:19010322
      supporting_text: "P70R-HA was localized to the endoplasmic"
- term:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: EC 7.6.2.8 (ABC-type vitamin B12 transporter) mapped to the specific GO
      molecular function. This matches the experimentally demonstrated cobalamin
      transport activity of ABCD4.
    action: ACCEPT
    reason: This is the core molecular function of ABCD4, independently supported by
      direct in vitro transport assays. The EC-to-GO mapping is correct.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from InterPro transmembrane-domain signatures.
      Correct but uninformative given the specific lysosomal/ER membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: ABCD4 is a multi-pass membrane protein, so "membrane" is not wrong, but it
      is subsumed by the more specific lysosomal membrane and ER membrane annotations
      and adds no information.
    supported_by:
    - reference_id: file:human/ABCD4/ABCD4-uniprot.txt
      supporting_text: Lysosome membrane {ECO
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP hydrolysis activity from InterPro ABC ATP-binding domain signatures.
      Directly supported by ATPase assays on purified, reconstituted ABCD4.
    action: ACCEPT
    reason: Reconstituted ABCD4 exhibits ATPase activity that is stimulated by luminal
      cobalamin and abolished by the Walker A K427A mutation, confirming ATP hydrolysis
      as an intrinsic activity coupled to transport.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: the cobalamin inside liposomes is recognized by ABCD4 as substrate
        and stimulates the ATP hydrolysis of ABCD4
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic transmembrane transport from InterPro. Correct but far more general
      than the specific cobalamin transport process ABCD4 mediates.
    action: MARK_AS_OVER_ANNOTATED
    reason: ABCD4 does mediate transmembrane transport, but this is a high-level parent
      of the specific and better-supported cobalamin transport annotation; it is
      uninformative on its own.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0140359
    label: ABC-type transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: General ABC-type transporter activity from InterPro ABC signatures. True
      but more general than the specific ABC-type vitamin B12 transporter activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: ABCD4 is an ABC-type transporter, so the term is not wrong, but the
      substrate-specific GO:0015420 (ABC-type vitamin B12 transporter activity) is
      experimentally established and preferred; this parent term over-annotates.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27456980
  qualifier: enables
  review:
    summary: IPI capturing the ABCD4-LMBD1 (LMBRD1, Q9NUN5) interaction. This is a
      functionally important interaction (LMBD1 escorts ABCD4 from the ER to the
      lysosome), but the bare "protein binding" term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction with LMBD1 is real and biologically central, but
      "protein binding" conveys no specific molecular function. Per curation guidelines,
      such bare GO:0005515 IPIs should not be treated as core; the functional partnership
      is captured in the description and core functions.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "this translocation depends on the lysosomal targeting ability of"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Bare "protein binding" IPI from a proteome-scale interactome screen
      (BioPlex) capturing the FAM234B (A2RU67) interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome hit with an uninformative term; no specific
      molecular function is defined and the physiological relevance of the FAM234B hit
      is unestablished.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities
        and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28572511
  qualifier: enables
  review:
    summary: IPI capturing the ABCD4-LMBD1 interaction demonstrated by a live-cell FRET
      assay. Functionally important but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The ABCD4-LMBD1 interaction is real and central to ABCD4 targeting and
      function, but "protein binding" is non-informative; the partnership is captured
      elsewhere in the review.
    supported_by:
    - reference_id: PMID:28572511
      supporting_text: "we demonstrated selective"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare "protein binding" IPI from a proteome-scale interactome screen
      (BioPlex 3.0) capturing the FAM234B (A2RU67) interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome hit with an uninformative term; no specific
      molecular function is defined.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of
        the human interactome.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:27456980
  qualifier: enables
  review:
    summary: Self-interaction (homodimerization) of ABCD4, consistent with its function
      as a half-size ABC transporter that operates as a homodimer.
    action: KEEP_AS_NON_CORE
    reason: ABCD4 is a half-transporter that assembles into a homodimer to form the
      functional unit, so identical protein binding is genuine and biologically
      meaningful, but it is a structural/assembly property rather than the core
      catalytic function.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: consistent in mass with dimeric ABCD4
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Self-interaction of ABCD4 detected in a multimodal cell-mapping/interactome
      study, consistent with homodimer assembly.
    action: KEEP_AS_NON_CORE
    reason: Supports the homodimeric assembly of ABCD4; genuine but a structural
      property rather than the core transport function.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional
        genomics.
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758881
  qualifier: involved_in
  review:
    summary: Reactome-asserted involvement in cobalamin transport (dietary cobalamin
      uptake pathway). This is the core biological process of ABCD4.
    action: ACCEPT
    reason: Cobalamin transport across the lysosomal membrane is the established core
      role of ABCD4, independently supported by experimental transport and disease data.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 plays a key role in the transport of cobalamin from the
        lysosomal lumen to the cytosol
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9758890
  qualifier: involved_in
  review:
    summary: Reactome-asserted involvement in cobalamin transport (transport of RCbl
      within the body). Core biological process of ABCD4.
    action: ACCEPT
    reason: Duplicate assertion of the core cobalamin-transport role from a related
      Reactome pathway; well supported by experimental and clinical evidence.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 plays a key role in the transport of cobalamin from the
        lysosomal lumen to the cytosol
- term:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  evidence_type: EXP
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    summary: Direct in vitro demonstration that purified, reconstituted ABCD4 transports
      cobalamin across liposomal membranes in an ATP-dependent manner. This is the
      definitive core molecular function.
    action: ACCEPT
    reason: The strongest evidence for ABCD4's function - reconstituted ABCD4 transports
      cobalamin (Km 426 uM), the activity is ATPase-dependent, and the Walker A K427A
      mutant abolishes both ATPase and transport. Defines the exact core MF.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:22922874
  qualifier: located_in
  review:
    summary: Experimental demonstration that ABCD4 colocalizes with the lysosomal
      markers LAMP1 and LMBD1, establishing lysosomal membrane localization.
    action: ACCEPT
    reason: Directly supported experimental localization to the lysosomal membrane,
      the functional site of ABCD4's cobalamin-export activity.
    supported_by:
    - reference_id: PMID:22922874
      supporting_text: "in failure to release vitamin B12 from lysosomes, which mimics the cblF defect"
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:25535791
  qualifier: located_in
  review:
    summary: Lysosomal vitamin B12 transporter localization from the ABCD4/LMBD1
      purification and interaction study.
    action: ACCEPT
    reason: Consistent, well-supported lysosomal membrane localization; ABCD4 is one of
      the two lysosomal membrane B12 transporters characterized in this work.
    supported_by:
    - reference_id: PMID:25535791
      supporting_text: Mutations in human LMBRD1 and ABCD4 prevent lysosomal export of vitamin B(12) to
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:28572511
  qualifier: located_in
  review:
    summary: Lysosomal targeting of ABCD4 (dependent on LMBD1 co-expression) shown by
      live-cell assays.
    action: ACCEPT
    reason: Experimental support for lysosomal membrane localization; the study also
      shows this localization depends on interaction with LMBD1.
    supported_by:
    - reference_id: PMID:28572511
      supporting_text: "targeting depends on co-expression of, and interaction with, LMBD1. These data"
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:33845046
  qualifier: is_active_in
  review:
    summary: ABCD4 is active (transports cobalamin) at the lysosomal membrane, its
      physiological site of action.
    action: ACCEPT
    reason: The lysosomal membrane is where ABCD4 performs its cobalamin-export
      function; is_active_in is appropriate given the demonstrated transport activity
      and lysosomal localization.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 is located on lysosomal membrane
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:33845046
  qualifier: involved_in
  review:
    summary: ABCD4 participates in cobalamin metabolism by exporting lysosomal cobalamin
      to the cytosol for cofactor synthesis.
    action: ACCEPT
    reason: By delivering cobalamin to the cytosol for conversion to methylcobalamin and
      adenosylcobalamin, ABCD4 is a core component of intracellular cobalamin metabolism;
      directly supported.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: "cobalamin is released into the cytosol and converted into two active cofactors: methylcobalamin and adenosylcobalamin"
- term:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  evidence_type: IDA
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    summary: Direct-assay support (IDA) for the ABC-type vitamin B12 transporter
      activity of ABCD4. Core molecular function.
    action: ACCEPT
    reason: Same definitive in vitro transport evidence; the exact GOA MF term for
      ABCD4's core function.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:33845046
  qualifier: located_in
  review:
    summary: Direct-assay lysosomal membrane localization of ABCD4.
    action: ACCEPT
    reason: Consistent with all other experimental evidence for lysosomal membrane
      localization.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 is located on lysosomal membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    summary: IPI capturing the ABCD4-LMBD1 (Q9NUN5) interaction from the in vitro
      pull-down/crosslinking analyses. Functionally central but the bare term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The purified ABCD4-LMBD1 interaction (1:1 stoichiometry) is genuine and
      biologically important, but "protein binding" is a non-informative term; the
      partnership is captured in the description and core functions.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: purified ABCD4 and LMBD1 interact each other with a 1:1 stoichiometry
- term:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  evidence_type: IMP
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    summary: Mutant-phenotype support (IMP) for the ABC-type vitamin B12 transporter
      activity - disease and engineered mutations abolish cobalamin transport.
    action: ACCEPT
    reason: Loss-of-function mutations (e.g. Walker A K427A, clinical Y319C) abolish
      cobalamin transport, providing mutant-phenotype evidence for this core molecular
      function.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 (K427A) had lost transport activity in addition to ATPase activity
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IMP
  original_reference_id: PMID:33845046
  qualifier: involved_in
  review:
    summary: Mutant-phenotype support for ABCD4's role in cobalamin transport. Core
      biological process.
    action: ACCEPT
    reason: Mutations that impair ABCD4 abolish cobalamin transport across the lysosomal
      membrane, directly implicating ABCD4 in this process.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 plays a key role in the transport of cobalamin from the
        lysosomal lumen to the cytosol
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: located_in
  review:
    summary: Direct-assay lysosomal membrane localization; ABCD4 localizes to lysosomes
      upon LMBD1-mediated translocation from the ER.
    action: ACCEPT
    reason: Well-supported experimental localization; the study establishes that
      lysosomal localization is achieved via LMBD1-dependent translocation.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "this translocation depends on the lysosomal targeting ability of"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: located_in
  review:
    summary: Direct-assay ER membrane localization; ABCD4 is an ER-resident protein
      before LMBD1-dependent lysosomal targeting.
    action: ACCEPT
    reason: Experimentally demonstrated ER localization (biosynthetic-intermediate site);
      endogenous ABCD4 distributes between ER and lysosome, with LMBD1 controlling the
      lysosomal fraction.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25535791
  qualifier: enables
  review:
    summary: IPI capturing the ABCD4 interactions with LMBD1 (Q9NUN5) and MMACHC (Q9Y4U1)
      from SPR/biophysical analyses. Both are functionally central (lysosomal
      cobalamin-to-cytosol trafficking complex), but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The ABCD4-LMBD1 and ABCD4-MMACHC interactions (both low nanomolar affinity)
      are genuine and important for vectorial cobalamin delivery, but "protein binding"
      is non-informative; the interactions are captured in the description and core
      functions.
    supported_by:
    - reference_id: PMID:25535791
      supporting_text: "LMBD1 and ABCD4 interact with low"
    - reference_id: PMID:25535791
      supporting_text: MMACHC also interacts with LMBD1 and ABCD4 with low nanomolar affinity.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:19010322
  qualifier: located_in
  negated: true
  review:
    summary: NOT annotation - ABCD4 does NOT localize to peroxisomes. This study showed
      P70R/ABCD4 localizes to the ER, not peroxisomes.
    action: ACCEPT
    reason: Correct negative annotation directly supported by the primary data
      overturning the original peroxisomal assignment.
    supported_by:
    - reference_id: PMID:19010322
      supporting_text: "reticulum (ER), not to peroxisomes."
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: located_in
  negated: true
  review:
    summary: NOT annotation - ABCD4 does NOT localize to peroxisomes; it is an ER/lysosomal
      protein.
    action: ACCEPT
    reason: Correct negative annotation; the study explicitly shows ABCD4 is not a
      peroxisomal protein.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:14533738
  qualifier: located_in
  review:
    summary: Positive peroxisome localization reflecting the superseded early view of
      ABCD4 as a peroxisomal half-transporter. This paper is principally about ALDP
      (ABCD1) peroxisomal targeting and uses a PMP69/ABCD4 fragment fused to reporter.
    action: REMOVE
    reason: The peroxisomal localization of full-length ABCD4 has been overturned by
      subsequent direct evidence (ER/lysosome; NOT|peroxisome IDAs; UniProt CAUTION).
      This positive peroxisome annotation is contradicted by the current consensus and
      should be removed in favor of the negated peroxisome and lysosomal annotations.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: "ABCD4 was not a peroxisomal protein, but rather, an ER protein"
    - reference_id: PMID:19010322
      supporting_text: "reticulum (ER), not to peroxisomes."
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9302272
  qualifier: located_in
  review:
    summary: Original identification of ABCD4 (P70R) as a fourth half ABC transporter in
      the human peroxisomal membrane - the initial, now-superseded peroxisomal
      assignment.
    action: REMOVE
    reason: This early peroxisomal-membrane localization has been overturned; ABCD4 is
      an ER/lysosomal protein lacking a peroxisomal targeting signal (UniProt CAUTION;
      PMID:19010322, PMID:27456980). The positive peroxisome annotation is contradicted
      by the subsequent NOT|peroxisome experimental data.
    supported_by:
    - reference_id: PMID:19010322
      supporting_text: "reticulum (ER), not to peroxisomes."
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5683325
  qualifier: located_in
  review:
    summary: Reactome-asserted lysosomal membrane localization (defective-transport
      event). Consistent with all experimental localization data.
    action: ACCEPT
    reason: Correct lysosomal membrane localization, agreeing with the direct
      experimental evidence.
    supported_by:
    - reference_id: PMID:22922874
      supporting_text: "in failure to release vitamin B12 from lysosomes, which mimics the cblF defect"
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5223313
  qualifier: located_in
  review:
    summary: Reactome-asserted lysosomal membrane localization (RCbl transport in gut
      mucosal cells). Consistent with experimental data.
    action: ACCEPT
    reason: Correct lysosomal membrane localization.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 is located on lysosomal membrane
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759206
  qualifier: located_in
  review:
    summary: Reactome-asserted lysosomal membrane localization (ABCD4-LMBRD1 transports
      RCbl from lysosomal lumen to cytosol). Consistent with experimental data.
    action: ACCEPT
    reason: Correct lysosomal membrane localization, matching the functional
      ABCD4-LMBRD1 export event.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 is located on lysosomal membrane
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IMP
  original_reference_id: PMID:22922874
  qualifier: involved_in
  review:
    summary: Mutant-phenotype support for ABCD4's role in cobalamin metabolism -
      mutations cause a new inborn error of vitamin B12 metabolism (cblJ).
    action: ACCEPT
    reason: ABCD4 mutations cause failure to release cobalamin from lysosomes and
      impaired cofactor synthesis, directly implicating ABCD4 in cobalamin metabolism.
    supported_by:
    - reference_id: PMID:22922874
      supporting_text: "the ATPase activity of ABCD4 may"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: NAS
  original_reference_id: PMID:9266848
  qualifier: enables
  review:
    summary: Author statement of ATP binding based on the ABC-half-transporter sequence
      identification. Consistent with the experimentally confirmed nucleotide-binding
      domain.
    action: ACCEPT
    reason: ATP binding is supported by the canonical ABC nucleotide-binding domain and
      by subsequent ATPase-dependent transport assays; the NAS assertion is correct.
    supported_by:
    - reference_id: PMID:9266848
      supporting_text: "ABC-half-transporters require a partner"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:9266848
  qualifier: located_in
  review:
    summary: Author statement of membrane localization from the original cloning paper.
      Generic; subsumed by the specific lysosomal/ER membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: ABCD4 is a membrane protein, so this is not wrong, but the term is
      uninformative relative to the specific lysosomal membrane and ER membrane
      annotations.
    supported_by:
    - reference_id: file:human/ABCD4/ABCD4-uniprot.txt
      supporting_text: Lysosome membrane {ECO
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: NAS
  original_reference_id: PMID:9266848
  qualifier: enables
  review:
    summary: Author-stated ABC (ATPase-coupled) transporter activity from the original
      cloning paper. Correct at the family level but more general than the demonstrated
      cobalamin-specific activity.
    action: MODIFY
    reason: The essence (ATP-driven transmembrane transport) is correct, but the specific
      ABC-type vitamin B12 transporter activity is now experimentally established and
      should be used.
    proposed_replacement_terms:
    - id: GO:0015420
      label: ABC-type vitamin B12 transporter activity
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
- term:
    id: GO:0043190
    label: ATP-binding cassette (ABC) transporter complex
  evidence_type: NAS
  original_reference_id: PMID:9266848
  qualifier: part_of
  review:
    summary: Author statement that ABCD4 is part of an ABC transporter complex. ABCD4 is
      a half-transporter that functions as a homodimer (and associates with LMBD1), so
      it is part of an ABC transporter complex.
    action: ACCEPT
    reason: As a half-size ABC transporter, ABCD4 assembles into a homodimeric functional
      complex, consistent with this cellular-component annotation.
    supported_by:
    - reference_id: PMID:9266848
      supporting_text: "ABC-half-transporter to constitute a functional complex, either as a homodimer"
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:9266848
  qualifier: involved_in
  review:
    summary: Author statement of transmembrane transport involvement. Correct but far
      more general than the specific cobalamin transport process.
    action: MARK_AS_OVER_ANNOTATED
    reason: ABCD4 mediates transmembrane transport, but this high-level parent is
      subsumed by the specific and better-supported cobalamin transport annotation.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
        in a manner that is dependent on ATPase activity
core_functions:
- description: ATP-dependent lysosomal cobalamin (vitamin B12) exporter that hydrolyzes
    ATP to translocate cobalamin from the lysosomal lumen to the cytosol, functioning as
    a homodimer at the lysosomal membrane.
  molecular_function:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  - id: GO:0009235
    label: cobalamin metabolic process
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:33845046
    supporting_text: ABCD4 transports cobalamin from the inside to the outside of liposomes
      in a manner that is dependent on ATPase activity
  - reference_id: file:human/ABCD4/ABCD4-uniprot.txt
    supporting_text: from the lysosomal lumen to the cytosol in an ATP-dependent manner
- description: Intrinsic ATPase / nucleotide-binding activity of the ABC transporter
    nucleotide-binding domain that energizes cobalamin transport; ATP binding and
    hydrolysis are coupled to substrate translocation (Walker A K427 is essential).
  molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:33845046
    supporting_text: the cobalamin inside liposomes is recognized by ABCD4 as substrate
      and stimulates the ATP hydrolysis of ABCD4
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  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:14533738
  title: Targeting of the human adrenoleukodystrophy protein to the peroxisomal membrane
    by an internal region containing a highly conserved motif.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: Study is about ALDP (ABCD1) peroxisomal targeting; cited to support a
      peroxisomal localization of ABCD4/PMP69 that is now superseded. Does not support
      full-length ABCD4 being peroxisomal.
- id: PMID:19010322
  title: 70-kDa peroxisomal membrane protein related protein (P70R/ABCD4) localizes
    to endoplasmic reticulum not peroxisomes, and NH2-terminal hydrophobic property
    determines the subcellular localization of ABC subfamily D proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes that ABCD4 (P70R) localizes to the ER, not peroxisomes,
      and that it lacks the N-terminal signal used for peroxisomal targeting.
- id: PMID:22922874
  title: Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational disease paper (cblJ); shows ABCD4 colocalizes with LAMP1
      and LMBD1 and that ATPase-domain mutations impair function. Abstract-only in cache.
- id: PMID:25535791
  title: 'Purification and interaction analyses of two human lysosomal vitamin B12
    transporters: LMBD1 and ABCD4.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Purified ABCD4 and LMBD1 form homodimers and interact with low
      nanomolar affinity; MMACHC also interacts, supporting a vectorial delivery model.
- id: PMID:27456980
  title: Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum
    to lysosomes requires the escort protein LMBD1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes LMBD1-dependent ER-to-lysosome translocation of ABCD4 and
      that ABCD4 is not peroxisomal; endogenous ABCD4 splits between ER and lysosome.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale (BioPlex) interactome; source of a bare protein-binding
      IPI (FAM234B). No specific ABCD4 function established.
- id: PMID:28572511
  title: Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between
    the vitamin B(12)-trafficking proteins ABCD4 and LMBD1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: FRET assay shows selective ABCD4-LMBD1 interaction disrupted by clinical
      or ATPase-domain mutations; lysosomal targeting depends on LMBD1 interaction.
- id: PMID:33845046
  title: The lysosomal protein ABCD4 can transport vitamin B(12) across liposomal
    membranes in vitro.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive functional paper - reconstituted ABCD4 transports cobalamin
      ATP-dependently (Km 426 uM); Walker A K427A abolishes ATPase and transport.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale (BioPlex 3.0) interactome; source of a bare
      protein-binding IPI (FAM234B). No specific ABCD4 function established.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal interactome/cell-mapping study; source of an identical
      protein binding (self/homodimer) IPI. No specific ABCD4 function beyond assembly.
- id: PMID:9266848
  title: Primary structure of human PMP69, a putative peroxisomal ABC-transporter.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original cloning of ABCD4 (PMP69) as a putative peroxisomal
      ABC-half-transporter; the peroxisomal assignment was later superseded.
- id: PMID:9302272
  title: Identification of a fourth half ABC transporter in the human peroxisomal
    membrane.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: DISPUTED
    review_notes: Original identification of ABCD4 (P70R) as a peroxisomal half ABC
      transporter; the peroxisomal-membrane localization was overturned by later work.
- id: Reactome:R-HSA-5223313
  title: ABCD4:LMBRD1 transports RCbl from lysosomal lumen to cytosol (gut mucosal
    cells)
  findings: []
- id: Reactome:R-HSA-5683325
  title: Defective ABCD4:LMBRD1 does not transport Cbl from lysosomal lumen to cytosol
  findings: []
- id: Reactome:R-HSA-9758881
  title: Uptake of dietary cobalamins into enterocytes
  findings: []
- id: Reactome:R-HSA-9758890
  title: Transport of RCbl within the body
  findings: []
- id: Reactome:R-HSA-9759206
  title: ABCD4:LMBRD1 transports RCbl from lysosomal lumen to cytosol
  findings: []
- id: file:human/ABCD4/ABCD4-uniprot.txt
  title: ABCD4 UniProtKB record (O14678)
  findings: []

Gene Description

Existing Annotations Review

Core Functions

ATP-dependent lysosomal cobalamin (vitamin B12) exporter that hydrolyzes ATP to translocate cobalamin from the lysosomal lumen to the cytosol, functioning as a homodimer at the lysosomal membrane.

Intrinsic ATPase / nucleotide-binding activity of the ABC transporter nucleotide-binding domain that energizes cobalamin transport; ATP binding and hydrolysis are coupled to substrate translocation (Walker A K427 is essential).

References

📚 Additional Documentation

Notes

ABCD4 (O14678) review notes

Verified biology (grounded in UniProt O14678 + cached PMIDs)

Curation decisions

📄 View Raw YAML