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 the N-terminal hydrophilic region associated with peroxisomal targeting; 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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | REMOVE | Summary: Human ABCD4 follows an ER-to-lysosome targeting route and was experimentally excluded from peroxisomes. Reason: PTHR11384 places the peroxisomal-membrane IBD at PTN004256010. Target-specific localization and targeting experiments, rather than donor number or absent fatty-acid assays, challenge inheritance of that compartment in ABCD4. PMID:19010322 reports full-length P70R-HA in the ER rather than peroxisomes and identifies its divergent N-terminal targeting architecture; PMID:27456980 establishes endogenous ER/lysosome localization and LMBD1-dependent lysosomal delivery. These findings support rejecting native peroxisomal-membrane localization while preserving the two experimental NOT annotations. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET The ancestral peroxisomal ABC transporter node is challenged by direct ABCD4 localization and targeting divergence. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes PMID:19010322 only P70R lacks the region and is translated with NH(2)-terminal hydrophobic TMS1. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATPase-coupled transmembrane transporter activity accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS TRANSFER ABCD4 retains the ABC ATPase-coupled transport mechanism despite substrate and compartment divergence. 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: The inherited long-chain fatty acid transporter activity is unsupported for lysosomal ABCD4 and reflects paralog transfer from the peroxisomal ABCD1-3 transporters. Reason: ABCD4 is a divergent lysosomal cobalamin exporter rather than a native peroxisomal fatty-acid transporter. Primary localization work showed that P70R/ABCD4 lacks the ABCD1-3 N-terminal peroxisomal-targeting region, and the focused OpenScientist report found no ABCD4 fatty-acid substrate assay while tracing this term to an IBA-only transfer from the ABCD1-3 peroxisomal branch. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET The fatty-acid transporter assertion fits ABCD1-3 but not the divergent lysosomal cobalamin transporter ABCD4 branch. Supporting Evidence: PMID:19010322 only P70R lacks the region and is translated with NH(2)-terminal hydrophobic TMS1. file:human/ABCD4/ABCD4-hypotheses/fatty-acid-functions-and-peroxisome-organization/openscientist.md None of the four claims has any experimental support on ABCD4 |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | REMOVE | Summary: The inherited fatty acid beta-oxidation process is ABCD1-3 paralog carry-over and is not supported as a direct ABCD4 process. Reason: Direct ABCD4 localization work excluded the native peroxisomal compartment used by ABCD1-3 acyl-CoA importers, and ABCD4's supported process is lysosomal cobalamin export rather than peroxisomal fatty-acid oxidation. The OpenScientist report recommended this IBA-only row as a candidate removal rather than proving fatty-acyl transport impossible; because the peroxisomal import step is unsupported for ABCD4, there is no mechanistic route for a direct ABCD4 role in beta-oxidation. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET The peroxisomal beta-oxidation assertion fits ABCD1-3 but not ER/lysosomal ABCD4. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes file:human/ABCD4/ABCD4-hypotheses/fatty-acid-functions-and-peroxisome-organization/openscientist.md GO:0006635 fatty acid β-oxidation | BP | IBA only | **Non-core / candidate removal.** No pathway participation shown for ABCD4. |
| GO:0015910 long-chain fatty acid import into peroxisome | IBA GO_REF:0000033 | REMOVE | Summary: ABCD4 does not support the assigned role of importing long-chain fatty acids across the peroxisomal membrane. Reason: This is a compartment-specific transport claim placed at PTN004256010. Direct ABCD4 targeting/localization experiments show an ER-to-lysosome itinerary and exclude the peroxisomal membrane in the studied context. That target-specific compartment divergence challenges peroxisomal import, independently of whether ABCD4 has any untested fatty-acid transport capacity in other membranes. Do not generalize this rejection into proof of absent fatty-acid chemistry. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET ABCD4 diverged in targeting from the ancestral peroxisomal transporter context. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes PMID:19010322 only P70R lacks the region and is translated with NH(2)-terminal hydrophobic TMS1. |
| GO:0042760 very long-chain fatty acid catabolic process | IBA GO_REF:0000033 | REMOVE | Summary: The inherited very-long-chain fatty acid catabolic process assertion is unsupported for ABCD4 and reflects over-propagation from the peroxisomal ABCD1-3 fatty-acid transporters. Reason: ABCD4's supported process is lysosomal cobalamin export and downstream cobalamin metabolism, and direct localization work places it outside the peroxisome where ABCD1-3 initiate VLCFA breakdown. The OpenScientist report treated this IBA-only pathway row as a candidate removal; because ABCD4 has neither a supported fatty-acyl-CoA transport step nor native peroxisomal residence, the VLCFA catabolic-process assertion is unsupported. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET The source node describes the peroxisomal ABCD1-3 substrate branch; ABCD4 is the divergent lysosomal cobalamin exporter. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes file:human/ABCD4/ABCD4-hypotheses/fatty-acid-functions-and-peroxisome-organization/openscientist.md The fatty-acid β-oxidation and VLCFA claims are *pathway-level* processes that in ABCD1–3 follow acyl-CoA import into peroxisomes. For ABCD4 there is neither the transport step (no assay) nor the compartment (not peroxisomal), so any such role would be inference, not direct activity. |
| 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: The inherited peroxisome-organization assertion is contradicted by ABCD4's ER-to-lysosome targeting route. Reason: The focused OpenScientist report found no mechanistic basis for ABCD4 as a peroxisome-organization factor. The claim was propagated with the peroxisomal ABCD1-3 branch, while ABCD4 has direct ER/lysosome localization evidence and experimentally supported NOT-peroxisome annotations. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004256010 · PTN004256010 SUPPORTS SOURCE BUT NOT TARGET The peroxisome organization assertion should not transfer to a lysosomal transporter with target-specific NOT peroxisome evidence. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes file:human/ABCD4/ABCD4-hypotheses/fatty-acid-functions-and-peroxisome-organization/openscientist.md Peroxisome organization is an organelle-biogenesis process; ABCD4 is not a peroxisomal resident, removing the mechanistic basis for a direct role. |
| 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 | ACCEPT | Summary: membrane accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. 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: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 | ACCEPT | Summary: transmembrane transport accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. 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 | ACCEPT | Summary: ABC-type transporter activity accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. 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... | REMOVE | 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 generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. 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... | REMOVE | Summary: Bare "protein binding" IPI from a proteome-scale interactome screen (BioPlex) capturing the FAM234B (A2RU67) interaction. Reason: The generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. 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... | REMOVE | Summary: IPI capturing the ABCD4-LMBD1 interaction demonstrated by a live-cell FRET assay. Functionally important but the bare term is uninformative. Reason: The generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. Supporting Evidence: PMID:28572511 we demonstrated selective |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Bare "protein binding" IPI from a proteome-scale interactome screen (BioPlex 3.0) capturing the FAM234B (A2RU67) interaction. Reason: The generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. 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... | REMOVE | 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 generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. 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... | REMOVE | 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 generic protein binding label does not specify a separate molecular function. Retain the interaction observations, including the functional LMBD1 escort interaction where relevant, but remove this uninformative term without claiming that the physical interaction is false or inventing a new binding function. 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... | UNDECIDED | Summary: The 2003 paper reports peroxisomal targeting of GFP-labelled ABCD4 fragments, whereas later work places full-length ABCD4 in ER and lysosomes. Reason: PMID:14533738 explicitly includes human PMP69 fragments; it must not be dismissed because its title foregrounds ABCD1. Fragment targeting can coexist with full-length targeting determined by the N terminus, so the later negative localization assays do not by themselves falsify the reported construct result. The cached source is abstract-only; reconciliation requires the exact ABCD4 construct and localization evidence before deciding how that experimental observation should annotate the intact gene product. Supporting Evidence: PMID:14533738 Green fluorescent protein-labeled fragments of human peroxisomal membrane protein 69 |
| GO:0005777 peroxisome | IDA PMID:9302272 Identification of a fourth half ABC transporter in the human... | REMOVE | Summary: The early peroxisomal assignment is contradicted for intact human ABCD4 by later direct targeting and localization experiments. Reason: This is not a claim that the original paper assayed the wrong gene. PMID:27456980 explicitly revisits the older antibody-based rat hepatic peroxisome result and contrasts it with human ABCD4 expression/localization, then establishes endogenous ER/lysosome pools. Together with the targeting experiments in PMID:19010322, this supports withdrawing the general native-human peroxisome assignment. Species, antibody and construct context remain limitations of reconciling the historical experiment, whose full text is unavailable here. Supporting Evidence: PMID:27456980 ABCD4 does not localize to peroxisomes PMID:19010322 only P70R lacks the region and is translated with NH(2)-terminal hydrophobic TMS1. |
| 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... | ACCEPT | Summary: membrane accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. 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:0042626 ATPase-coupled transmembrane transporter activity | NAS PMID:9266848 Primary structure of human PMP69, a putative peroxisomal ABC... | ACCEPT | Summary: ATPase-coupled transmembrane transporter activity accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. 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... | ACCEPT | Summary: transmembrane transport accurately describes the membrane-embedded ABCD4 cobalamin transporter. Reason: Purified ABCD4 reconstituted in liposomes catalyzes ATP-dependent cobalamin translocation (PMID:33845046); localization experiments establish ER and lysosomal membranes (PMID:27456980). The broad transporter, transport and membrane terms are true core properties alongside the more specific vitamin-B12 transporter annotation. Greater specificity does not make these existing parent-level assertions over-annotations. Supporting Evidence: PMID:33845046 ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity |
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