LMBRD1 encodes LMBD1 (Lysosomal cobalamin transport escort protein LMBD1), a multi-pass glycosylated lysosomal membrane protein of the LIMR/LMBR1 family. It is required to export cobalamin (vitamin B12) from the lysosome to the cytosol after transcobalamin-bound cobalamin is endocytosed and degraded, making the vitamin available for cytosolic processing (by MMACHC/MMADHC) into the cofactors methylcobalamin and adenosylcobalamin. LMBD1 acts as an escort/chaperone for the half-ABC transporter ABCD4: it binds ABCD4 in the endoplasmic reticulum and is required to target and stabilize it at the lysosomal membrane, where the LMBD1:ABCD4 complex (handing off to cytosolic MMACHC) mediates ATP-dependent cobalamin efflux; the catalytic transport activity resides in ABCD4, while LMBD1 has no intrinsic cobalamin transport activity. Loss-of-function variants cause methylmalonic aciduria and homocystinuria, cblF type (MAHCF), in which free cobalamin accumulates in lysosomes. A minor plasma-membrane pool has been reported (mostly by similarity to the mouse ortholog) to act as a clathrin/AP-2 adaptor for internalization of the insulin receptor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of LMBD1 to the lysosomal membrane. This matches the strong direct experimental evidence for lysosomal membrane localization and is a core cellular component for this gene. Reason: LMBD1 is a bona fide lysosomal membrane protein, supported by multiple experimental studies (PMID:19136951, PMID:27456980, PMID:28572511, PMID:33845046). This is the core location of the protein. Supporting Evidence: PMID:27456980 The distribution of LMBD1-GFP coincided with that of LAMP1, i.e. having neither ER nor peroxisomal marker proteins (Fig. 1C), indicating that LMBD1-GFP is localized in lysosomes. |
| GO:0061462 protein localization to lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment that LMBD1 is involved in protein localization to the lysosome. This reflects the verified escort role of LMBD1 in targeting the ABCD4 transporter from the ER to the lysosome. Reason: LMBD1 is required to translocate ABCD4 from the ER to the lysosome and to retain it there; loss of LMBD1 disrupts ABCD4 lysosomal localization (PMID:27456980, PMID:28572511). This is a core molecular role of LMBD1 and is well captured by protein localization to lysosome. Supporting Evidence: PMID:27456980 our results support the view that the translocation of ABCD4 from the ER to lysosomes requires, at least in part, the lysosomal membrane protein LMBD1. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCellular-location (SL-0157, Lysosome membrane) IEA mapping to lysosomal membrane. Redundant with, and confirmed by, the experimental annotations. Reason: Correct location, well supported experimentally (see EXP/IDA entries). Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Lysosome membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCellular-location (SL-0097) IEA mapping to ER membrane. LMBD1 is present transiently in the ER membrane, where it binds newly synthesized ABCD4 before both traffic to the lysosome; this is a biosynthetic/mechanistic location rather than the steady-state functional compartment. Reason: ER-membrane localization is real (PMID:27456980 IDA) but represents the early biosynthetic step of the LMBD1/ABCD4 escort pathway, not the core lysosomal-membrane site of action. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Targets ABCD4 transporter from the |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined-methods IEA (with_from mouse ortholog Q8K0B2 SubCell SL-0039) placing LMBD1 at the plasma membrane. A minor plasma-membrane pool is reported in the mouse ortholog in the context of an insulin-receptor endocytosis adaptor role; human direct evidence is lacking. Reason: Only a small portion of LMBD1 is reported at the plasma membrane, and the supporting evidence is by similarity to the mouse ortholog. The core location is the lysosomal membrane. Keep as a non-core minor location. Supporting Evidence: PMID:27456980 recently a small region of LMBD1 was shown to be located on plasma membranes |
| GO:0015889 cobalamin transport | IEA GO_REF:0000108 | ACCEPT | Summary: Interontology (IEA, from MF GO:0015420) inference that LMBD1 is involved in cobalamin transport. LMBD1 is a subunit of the lysosomal cobalamin export complex and its loss (cblF) blocks lysosomal cobalamin efflux, so involvement in cobalamin transport is well supported at the process level. Reason: Cobalamin transport is the core biological process of LMBD1: loss of LMBD1 causes lysosomal cobalamin accumulation (cblF), and LMBD1 is an essential component of the LMBD1:ABCD4 lysosomal export complex (PMID:19136951, PMID:27456980). Supporting Evidence: PMID:27456980 ABCD4 and LMBD1, encoded by ABCD4 and LMBRD1 respectively, were shown to be involved in the export of cobalamin from lysosomes into the cytosol |
| GO:0030136 clathrin-coated vesicle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined-methods IEA (with_from mouse ortholog Q8K0B2, SubCell SL-0070) placing LMBD1 in clathrin-coated vesicles, tied to the by-similarity insulin-receptor endocytosis adaptor role. Reason: This location relates to the secondary, by-similarity clathrin-mediated endocytosis function (insulin receptor) rather than the core lysosomal cobalamin role. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle |
| GO:0035461 vitamin transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: Interontology (IEA, from MF GO:0090482) inference that LMBD1 is involved in vitamin transmembrane transport. This is the more general parent of the cobalamin (vitamin B12) transport process in which LMBD1 participates. Reason: Correct but less specific than cobalamin transport. Cobalamin is a vitamin (B12), so vitamin transmembrane transport is an accurate broader process term for the LMBD1:ABCD4 export function. Supporting Evidence: PMID:28572511 The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal |
| GO:0005515 protein binding | IPI PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | MARK AS OVER ANNOTATED | Summary: IPI protein binding annotation with_from ABCD4 (O14678), from the study demonstrating the LMBD1-ABCD4 interaction and ABCD4 escort to lysosomes. The interaction is real and functionally central, but "protein binding" is uninformative as a molecular function. Reason: The LMBD1-ABCD4 interaction is genuine and important (PMID:27456980), but the bare GO:0005515 protein binding term does not convey the specific escort/chaperone function. The functionally meaningful role is captured by protein localization to lysosome (GO:0061462) and the cobalamin transport process terms. Retain the interaction as evidence but treat the generic MF as an over-annotation. Supporting Evidence: PMID:27456980 These results show that ABCD4 is able to form a complex with LMBD1 in cells. |
| GO:0005515 protein binding | IPI PMID:28572511 Clinical or ATPase domain mutations in ABCD4 disrupt the int... | MARK AS OVER ANNOTATED | Summary: IPI protein binding annotation with_from ABCD4 (O14678), from the FRET-based confirmation of the selective ABCD4-LMBD1 interaction and its requirement for ABCD4 lysosomal targeting. Reason: Genuine and important LMBD1-ABCD4 interaction (PMID:28572511), but the generic protein binding MF is uninformative. The specific function is better represented by protein localization to lysosome and cobalamin transport. Supporting Evidence: PMID:28572511 we showed that ABCD4 lysosomal |
| GO:0007369 gastrulation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning involvement in gastrulation, reflecting an early embryonic role reported by similarity. Reason: A developmental/gastrulation role is asserted only by similarity to the mouse ortholog and is not part of the core, biochemically defined lysosomal cobalamin function. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Essential for the initiation of gastrulation and early formation of mesoderm structures during embryogenesis |
| GO:0032050 clathrin heavy chain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning clathrin heavy chain binding, part of the by-similarity insulin-receptor clathrin-mediated endocytosis adaptor role. Reason: Related to the secondary, by-similarity endocytic-adaptor function rather than the core lysosomal cobalamin role; human direct evidence is absent. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0035612 AP-2 adaptor complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning AP-2 adaptor complex binding, consistent with the two putative AP-2 binding motifs (YERL and WTKF) noted in UniProt. Reason: Part of the by-similarity clathrin/AP-2 endocytic-adaptor role for the insulin receptor rather than the core cobalamin function. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 possesses two putative AP-2 binding motifs |
| GO:0038016 insulin receptor internalization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning involvement in insulin receptor internalization, the endpoint of the by-similarity clathrin-mediated endocytosis adaptor role. Reason: Secondary, by-similarity role (adaptor for INSR endocytosis); not the core lysosomal cobalamin function. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0072583 clathrin-dependent endocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning involvement in clathrin-dependent endocytosis (the INSR adaptor role). Reason: Secondary, by-similarity endocytic role; not the core cobalamin function. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0015420 ABC-type vitamin B12 transporter activity | IDA PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro... | MARK AS OVER ANNOTATED | Summary: IDA (via MGI) assigning ABC-type vitamin B12 transporter activity to LMBD1, from the liposome reconstitution study. However, that very study showed the transporter activity resides in ABCD4 and that LMBD1 by itself has no cobalamin transport (or ATPase) activity, so this MF is mis-attributed to LMBD1 as an enabler. Reason: PMID:33845046 demonstrated that ABCD4 alone transports cobalamin in an ATP-dependent manner and that LMBD1 exhibited no cobalamin transport activity; LMBD1 lacks nucleotide-binding domains and is not an ABC transporter. LMBD1 is a subunit/escort of the transporting complex, so ABC-type vitamin B12 transporter activity should not be annotated as a function LMBD1 enables. Not removed because LMBD1 is a genuine component of the cobalamin-transporting LMBD1:ABCD4 complex; the activity is better attributed to ABCD4 (or the complex). Supporting Evidence: PMID:33845046 no cobalamin transport activity. These results suggest that ABCD4 may be capable PMID:33845046 LMBD1 itself had neither ATPase nor cobalamin transport activities |
| GO:0090482 vitamin transmembrane transporter activity | IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | MARK AS OVER ANNOTATED | Summary: IDA (via MGI) assigning vitamin transmembrane transporter activity to LMBD1, citing the ABCD4-escort paper. That paper does not demonstrate LMBD1-intrinsic transporter activity; it shows LMBD1 escorts ABCD4 to lysosomes. The intrinsic transporter activity is ABCD4's (PMID:33845046). Reason: No study demonstrates that LMBD1 itself is a transmembrane transporter; the direct in vitro test (PMID:33845046) found LMBD1 has no cobalamin transport activity. LMBD1 participates in transport as an escort/subunit of the LMBD1:ABCD4 complex, so an enabled transmembrane transporter MF is an over-annotation. Retained rather than removed because LMBD1 is part of the transporting complex. Supporting Evidence: PMID:33845046 LMBD1 itself had neither ATPase nor cobalamin transport activities |
| GO:0005765 lysosomal membrane | EXP PMID:19136951 Identification of a putative lysosomal cobalamin exporter al... | ACCEPT | Summary: Experimental (EXP) lysosomal membrane localization from the founding cblF study that identified LMBD1 as a lysosomal membrane protein. Reason: Direct experimental support that LMBD1 is a lysosomal membrane protein; core location. Supporting Evidence: PMID:19136951 LMBRD1, encoding LMBD1, a lysosomal membrane protein with homology to lipocalin membrane receptor LIMR |
| GO:0005765 lysosomal membrane | EXP PMID:28572511 Clinical or ATPase domain mutations in ABCD4 disrupt the int... | ACCEPT | Summary: Experimental (EXP) lysosomal membrane localization from the FRET-based ABCD4-LMBD1 interaction study. Reason: Core location confirmed experimentally; LMBD1 is an integral lysosomal membrane protein required for lysosomal cobalamin release. Supporting Evidence: PMID:28572511 The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal |
| GO:0005765 lysosomal membrane | EXP PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro... | ACCEPT | Summary: Experimental (EXP) lysosomal membrane localization from the liposome reconstitution study, which describes LMBD1 as the lysosomal membrane protein that complexes with ABCD4. Reason: Core lysosomal-membrane location, consistent across all functional studies. Supporting Evidence: PMID:33845046 The ABCD4 dimer then forms a complex with lysosomal membrane protein LMBD1, and this complex is translocated from the ER to lysosomes |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) placing LMBD1 at the plasma membrane, reflecting the reported minor plasma-membrane pool linked to the INSR endocytosis adaptor role. Reason: Minor location supported only by similarity; core location is the lysosomal membrane. Keep as non-core. Supporting Evidence: PMID:27456980 recently a small region of LMBD1 was shown to be located on plasma membranes |
| GO:0090482 vitamin transmembrane transporter activity | IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | MARK AS OVER ANNOTATED | Summary: Duplicate IDA (via MGI, older date) assigning vitamin transmembrane transporter activity to LMBD1 from the ABCD4-escort paper; same over-annotation issue as the other GO:0090482 entry. Reason: LMBD1 has no demonstrated intrinsic transporter activity (PMID:33845046); it escorts and complexes with ABCD4, which is the catalytic transporter. Over-annotation, not removed because LMBD1 is a subunit of the transporting complex. Supporting Evidence: PMID:33845046 LMBD1 itself had neither ATPase nor cobalamin transport activities |
| GO:0005515 protein binding | IPI PMID:33845046 The lysosomal protein ABCD4 can transport vitamin B(12) acro... | MARK AS OVER ANNOTATED | Summary: IPI protein binding annotation with_from ABCD4 (O14678), from the in vitro pull-down/crosslinking showing purified LMBD1 and ABCD4 interact with 1:1 stoichiometry. Reason: Real and specific LMBD1-ABCD4 interaction, but the bare protein binding MF is uninformative. The functionally meaningful roles are protein localization to lysosome and cobalamin transport (as complex subunit). Supporting Evidence: PMID:33845046 These results indicate that purified ABCD4 and LMBD1 interact each other with a 1:1 stoichiometry. |
| GO:0038016 insulin receptor internalization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in insulin receptor internalization (the by-similarity endocytic adaptor role). Reason: Secondary, by-similarity function; not the core lysosomal cobalamin role. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) with part_of qualifier placing LMBD1 at the plasma membrane; a minor location tied to the by-similarity INSR endocytosis role. Reason: Minor, by-similarity plasma-membrane location; core location is the lysosomal membrane. Keep as non-core. Supporting Evidence: PMID:27456980 recently a small region of LMBD1 was shown to be located on plasma membranes |
| GO:0007369 gastrulation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in gastrulation, an early embryonic role asserted by similarity. Reason: Developmental role supported only by similarity to the mouse ortholog; not part of the core cobalamin function. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Essential for the initiation of gastrulation and early formation of mesoderm structures during embryogenesis |
| GO:0030136 clathrin-coated vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) placing LMBD1 in clathrin-coated vesicles, tied to the by-similarity INSR endocytosis adaptor role. Reason: Related to the secondary endocytic-adaptor function, by similarity; not the core lysosomal cobalamin role. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle |
| GO:0032050 clathrin heavy chain binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) assigning clathrin heavy chain binding (by-similarity INSR endocytic adaptor role). Reason: Secondary, by-similarity endocytic-adaptor function; not the core cobalamin role. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0035612 AP-2 adaptor complex binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) assigning AP-2 adaptor complex binding, consistent with the YERL/WTKF AP-2 binding motifs. Reason: Part of the by-similarity clathrin/AP-2 endocytic-adaptor role; not the core cobalamin function. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt YERL motif; mediates interaction with adapter |
| GO:0045334 clathrin-coated endocytic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) placing LMBD1 in clathrin-coated endocytic vesicles, tied to the by-similarity INSR endocytosis adaptor role. Reason: Related to the secondary endocytic-adaptor function, by similarity; not the core lysosomal cobalamin role. Keep as non-core. Supporting Evidence: file:human/LMBRD1/LMBRD1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle |
| GO:0072583 clathrin-dependent endocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in clathrin-dependent endocytosis (INSR adaptor role). Reason: Secondary, by-similarity endocytic role; not the core cobalamin function. Keep as non-core. Supporting Evidence: PMID:27456980 LMBD1 is reported to be a specific adaptor for the clathrin-mediated endocytosis of the insulin receptor |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | KEEP AS NON CORE | Summary: Direct (IDA) ER-membrane localization from the ABCD4-escort study; LMBD1 binds newly synthesized ABCD4 in the ER before both traffic to the lysosome. Reason: ER localization is genuine but is the transient biosynthetic step of the escort pathway, not the steady-state functional compartment (the lysosomal membrane). Keep as non-core. Supporting Evidence: PMID:27456980 This suggests that LMBD1 associates with ABCD4 at the ER membrane and transports ABCD4 to lysosomes. |
| GO:0005765 lysosomal membrane | IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | ACCEPT | Summary: Direct (IDA) lysosomal membrane localization from the ABCD4-escort study (LMBD1-GFP colocalizes with LAMP1). Core location. Reason: Strong direct experimental evidence for the core lysosomal membrane location. Supporting Evidence: PMID:27456980 indicating that LMBD1-GFP is localized in lysosomes |
| GO:0061462 protein localization to lysosome | IDA PMID:27456980 Translocation of the ABC transporter ABCD4 from the endoplas... | ACCEPT | Summary: Direct (IDA) evidence that LMBD1 is involved in protein localization to the lysosome, specifically escorting ABCD4 from the ER to the lysosome. This is a core, experimentally verified molecular role of LMBD1. Reason: LMBD1 is required to translocate and retain ABCD4 at the lysosomal membrane; mislocalized LMBD1 mutants fail to bring ABCD4 to lysosomes (PMID:27456980). Core function. Supporting Evidence: PMID:27456980 our results support the view that the translocation of ABCD4 from the ER to lysosomes requires, at least in part, the lysosomal membrane protein LMBD1. |
| GO:0005515 protein binding | IPI PMID:25535791 Purification and interaction analyses of two human lysosomal... | MARK AS OVER ANNOTATED | Summary: IPI protein binding annotations from the SPR study, with_from ABCD4 (O14678) and MMACHC (Q9Y4U1). LMBD1 binds both ABCD4 and the cytosolic cobalamin-processing protein MMACHC with low-nanomolar affinity, forming the complex that vectorially delivers lysosomal cobalamin to MMACHC. Real and functionally central interactions, but bare protein binding is uninformative as an MF. (The GOA has two lines for this PMID, one per partner; both are represented by this entry.) Reason: The LMBD1-ABCD4 and LMBD1-MMACHC interactions are genuine and important (PMID:25535791), but the generic GO:0005515 term does not capture the escort/hand-off function; that is better represented by protein localization to lysosome and the cobalamin transport process. Retain the interactions as evidence. Supporting Evidence: PMID:25535791 MMACHC also interacts with LMBD1 and ABCD4 with low nanomolar affinity. PMID:25535791 membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of lysosomal vitamin B(12) to cytoplasmic |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput (HDA) membrane-proteome identification of LMBD1 in an NK cell line, supporting a generic membrane localization. Reason: GO:0016020 membrane is a high-level, uninformative location from a proteomic membrane-fractionation screen; it is subsumed by the specific, experimentally supported lysosomal membrane annotation. Not wrong, but over-general. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-5223313 | ACCEPT | Summary: Reactome TAS lysosomal membrane localization from the ABCD4:LMBRD1 cobalamin export reaction (gut mucosal cells). Consistent with the core location. Reason: Curated pathway annotation consistent with all experimental evidence for lysosomal membrane localization. Supporting Evidence: Reactome:R-HSA-5223313 LMBRD1 stabilizes ABCD4 in the lysosomal membrane |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-5683325 | ACCEPT | Summary: Reactome TAS lysosomal membrane localization from the defective ABCD4:LMBRD1 cobalamin transport reaction. Consistent with the core location. Reason: Curated pathway annotation consistent with the experimentally established lysosomal membrane location. Supporting Evidence: Reactome:R-HSA-5683325 ATP-binding cassette sub-family D member 4 (ABCD4) is thought to mediate the lysosomal export of cobalamin |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-9759206 | ACCEPT | Summary: Reactome TAS lysosomal membrane localization from the ABCD4:LMBRD1 cobalamin export reaction (cells throughout the body). Consistent with the core location. Reason: Curated pathway annotation consistent with the experimentally established lysosomal membrane location. Supporting Evidence: Reactome:R-HSA-9759206 LMBRD1 stabilizes ABCD4 in the lysosomal membrane |
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Download this section (compressed HTML)Q: Given that LMBD1 has no intrinsic cobalamin transport or ATPase activity and ABCD4 alone suffices in vitro, is the correct molecular-function representation of LMBD1 a transporter-complex subunit / chaperone rather than an enabler of transporter activity, and should GO capture the LMBD1:ABCD4 (:MMACHC) complex explicitly?
Experiment: Cryo-EM or crystal structure of the lysosomal LMBD1:ABCD4 complex (with and without MMACHC) to define the LMBD1 interaction surface and the cobalamin hand-off path from the lysosomal lumen to cytosolic MMACHC.
Experiment: Reconstitution of the LMBD1:ABCD4:MMACHC assembly to test whether LMBD1 modulates the rate, directionality, or MMACHC-coupling of ABCD4-mediated cobalamin efflux beyond its established role in ABCD4 lysosomal targeting.
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