id: Q9NUN5
gene_symbol: LMBRD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q9NUN5-1
- name: '2'
  id: Q9NUN5-2
  sequence_note: VSP_021630, VSP_036540
- name: 3 (NESI)
  id: Q9NUN5-3
  sequence_note: VSP_021629
- name: '4'
  id: Q9NUN5-4
  sequence_note: VSP_036539, VSP_021630, VSP_036540
existing_annotations:
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        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.
- term:
    id: GO:0061462
    label: protein localization to lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        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.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCellular-location (SL-0157, Lysosome membrane) IEA mapping to
      lysosomal membrane. Redundant with, and confirmed by, the experimental
      annotations.
    action: ACCEPT
    reason: >-
      Correct location, well supported experimentally (see EXP/IDA entries).
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: "Lysosome membrane"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: "Targets ABCD4 transporter from the"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        recently a small region of LMBD1 was shown to be located on plasma
        membranes
- term:
    id: GO:0015889
    label: cobalamin transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        ABCD4 and LMBD1, encoded by ABCD4 and LMBRD1 respectively, were shown
        to be involved in the export of cobalamin from lysosomes into the
        cytosol
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: "Cytoplasmic vesicle, clathrin-coated vesicle"
- term:
    id: GO:0035461
    label: vitamin transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:28572511
      supporting_text: >-
        The integral membrane proteins LMBD1 and ABCD4 are required for
        lysosomal
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27456980
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        These results show that ABCD4 is able to form a complex with LMBD1 in
        cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28572511
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:28572511
      supporting_text: >-
        we showed that ABCD4 lysosomal
- term:
    id: GO:0007369
    label: gastrulation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning
      involvement in gastrulation, reflecting an early embryonic role reported
      by similarity.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: >-
        Essential for the initiation of gastrulation and early formation of
        mesoderm structures during embryogenesis
- term:
    id: GO:0032050
    label: clathrin heavy chain binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0035612
    label: AP-2 adaptor complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 possesses two putative AP-2 binding motifs
- term:
    id: GO:0038016
    label: insulin receptor internalization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary, by-similarity role (adaptor for INSR endocytosis); not the
      core lysosomal cobalamin function. Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara IEA transfer from the mouse ortholog (Q8K0B2) assigning
      involvement in clathrin-dependent endocytosis (the INSR adaptor role).
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary, by-similarity endocytic role; not the core cobalamin function.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0015420
    label: ABC-type vitamin B12 transporter activity
  evidence_type: IDA
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: >-
        no cobalamin transport activity. These results suggest that ABCD4 may
        be capable
    - reference_id: PMID:33845046
      supporting_text: >-
        LMBD1 itself had neither ATPase nor cobalamin transport activities
- term:
    id: GO:0090482
    label: vitamin transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: enables
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: >-
        LMBD1 itself had neither ATPase nor cobalamin transport activities
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:19136951
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) lysosomal membrane localization from the founding cblF
      study that identified LMBD1 as a lysosomal membrane protein.
    action: ACCEPT
    reason: >-
      Direct experimental support that LMBD1 is a lysosomal membrane protein;
      core location.
    supported_by:
    - reference_id: PMID:19136951
      supporting_text: >-
        LMBRD1, encoding LMBD1, a lysosomal membrane protein with homology to
        lipocalin membrane receptor LIMR
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:28572511
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) lysosomal membrane localization from the FRET-based
      ABCD4-LMBD1 interaction study.
    action: ACCEPT
    reason: >-
      Core location confirmed experimentally; LMBD1 is an integral lysosomal
      membrane protein required for lysosomal cobalamin release.
    supported_by:
    - reference_id: PMID:28572511
      supporting_text: >-
        The integral membrane proteins LMBD1 and ABCD4 are required for
        lysosomal
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:33845046
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) lysosomal membrane localization from the liposome
      reconstitution study, which describes LMBD1 as the lysosomal membrane
      protein that complexes with ABCD4.
    action: ACCEPT
    reason: >-
      Core lysosomal-membrane location, consistent across all functional
      studies.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: >-
        The ABCD4 dimer then forms a complex with lysosomal membrane protein
        LMBD1, and this complex is translocated from the ER to lysosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Minor location supported only by similarity; core location is the
      lysosomal membrane. Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        recently a small region of LMBD1 was shown to be located on plasma
        membranes
- term:
    id: GO:0090482
    label: vitamin transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: >-
        LMBD1 itself had neither ATPase nor cobalamin transport activities
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33845046
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
    - reference_id: PMID:33845046
      supporting_text: >-
        These results indicate that purified ABCD4 and LMBD1 interact each
        other with a 1:1 stoichiometry.
- term:
    id: GO:0038016
    label: insulin receptor internalization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in
      insulin receptor internalization (the by-similarity endocytic adaptor
      role).
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary, by-similarity function; not the core lysosomal cobalamin role.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Minor, by-similarity plasma-membrane location; core location is the
      lysosomal membrane. Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        recently a small region of LMBD1 was shown to be located on plasma
        membranes
- term:
    id: GO:0007369
    label: gastrulation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in
      gastrulation, an early embryonic role asserted by similarity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Developmental role supported only by similarity to the mouse ortholog;
      not part of the core cobalamin function. Keep as non-core.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: >-
        Essential for the initiation of gastrulation and early formation of
        mesoderm structures during embryogenesis
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) placing LMBD1 in
      clathrin-coated vesicles, tied to the by-similarity INSR endocytosis
      adaptor role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Related to the secondary endocytic-adaptor function, by similarity; not
      the core lysosomal cobalamin role. Keep as non-core.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: "Cytoplasmic vesicle, clathrin-coated vesicle"
- term:
    id: GO:0032050
    label: clathrin heavy chain binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) assigning clathrin heavy
      chain binding (by-similarity INSR endocytic adaptor role).
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary, by-similarity endocytic-adaptor function; not the core
      cobalamin role. Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0035612
    label: AP-2 adaptor complex binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) assigning AP-2 adaptor
      complex binding, consistent with the YERL/WTKF AP-2 binding motifs.
    action: KEEP_AS_NON_CORE
    reason: >-
      Part of the by-similarity clathrin/AP-2 endocytic-adaptor role; not the
      core cobalamin function. Keep as non-core.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: >-
        YERL motif; mediates interaction with adapter
- term:
    id: GO:0045334
    label: clathrin-coated endocytic vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) placing LMBD1 in
      clathrin-coated endocytic vesicles, tied to the by-similarity INSR
      endocytosis adaptor role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Related to the secondary endocytic-adaptor function, by similarity; not
      the core lysosomal cobalamin role. Keep as non-core.
    supported_by:
    - reference_id: file:human/LMBRD1/LMBRD1-uniprot.txt
      supporting_text: "Cytoplasmic vesicle, clathrin-coated vesicle"
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from the mouse ortholog (Q8K0B2) assigning involvement in
      clathrin-dependent endocytosis (INSR adaptor role).
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary, by-similarity endocytic role; not the core cobalamin function.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        LMBD1 is reported to be a specific adaptor for the clathrin-mediated
        endocytosis of the insulin receptor
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        This suggests that LMBD1 associates with ABCD4 at the ER membrane and
        transports ABCD4 to lysosomes.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) lysosomal membrane localization from the ABCD4-escort study
      (LMBD1-GFP colocalizes with LAMP1). Core location.
    action: ACCEPT
    reason: >-
      Strong direct experimental evidence for the core lysosomal membrane
      location.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        indicating that LMBD1-GFP is localized in lysosomes
- term:
    id: GO:0061462
    label: protein localization to lysosome
  evidence_type: IDA
  original_reference_id: PMID:27456980
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27456980
      supporting_text: >-
        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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25535791
  qualifier: enables
  review:
    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.)
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25535791
      supporting_text: >-
        MMACHC also interacts with LMBD1 and ABCD4 with low nanomolar affinity.
    - reference_id: PMID:25535791
      supporting_text: >-
        membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of
        lysosomal vitamin B(12) to cytoplasmic
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HDA) membrane-proteome identification of LMBD1 in an NK
      cell line, supporting a generic membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        Mass spectrometric analysis identified 1843 proteins with high
        confidence scores.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5223313
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS lysosomal membrane localization from the ABCD4:LMBRD1
      cobalamin export reaction (gut mucosal cells). Consistent with the core
      location.
    action: ACCEPT
    reason: >-
      Curated pathway annotation consistent with all experimental evidence for
      lysosomal membrane localization.
    supported_by:
    - reference_id: Reactome:R-HSA-5223313
      supporting_text: >-
        LMBRD1 stabilizes ABCD4 in the lysosomal membrane
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5683325
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS lysosomal membrane localization from the defective
      ABCD4:LMBRD1 cobalamin transport reaction. Consistent with the core
      location.
    action: ACCEPT
    reason: >-
      Curated pathway annotation consistent with the experimentally established
      lysosomal membrane location.
    supported_by:
    - reference_id: Reactome:R-HSA-5683325
      supporting_text: >-
        ATP-binding cassette sub-family D member 4 (ABCD4) is thought to
        mediate the lysosomal export of cobalamin
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759206
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS lysosomal membrane localization from the ABCD4:LMBRD1
      cobalamin export reaction (cells throughout the body). Consistent with
      the core location.
    action: ACCEPT
    reason: >-
      Curated pathway annotation consistent with the experimentally established
      lysosomal membrane location.
    supported_by:
    - reference_id: Reactome:R-HSA-9759206
      supporting_text: >-
        LMBRD1 stabilizes ABCD4 in the lysosomal membrane
core_functions:
- description: >-
    Lysosomal-membrane escort/chaperone that targets and stabilizes the ABC
    transporter ABCD4 at the lysosomal membrane (translocating it from the ER),
    thereby enabling assembly of the lysosomal cobalamin export machinery.
  directly_involved_in:
  - id: GO:0061462
    label: protein localization to lysosome
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:27456980
    supporting_text: >-
      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.
  - reference_id: PMID:28572511
    supporting_text: >-
      we showed that ABCD4 lysosomal
- description: >-
    As a subunit of the lysosomal LMBD1:ABCD4 complex (handing off to cytosolic
    MMACHC), participates in the export of cobalamin (vitamin B12) from the
    lysosomal lumen to the cytosol. LMBD1 has no intrinsic transport activity;
    the catalytic transport is performed by ABCD4. Loss of LMBD1 causes
    lysosomal cobalamin accumulation (cblF).
  directly_involved_in:
  - id: GO:0015889
    label: cobalamin transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:19136951
    supporting_text: >-
      In the cblF inborn error of vitamin B(12)
  - reference_id: PMID:25535791
    supporting_text: >-
      membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of
      lysosomal vitamin B(12) to cytoplasmic
  - reference_id: PMID:33845046
    supporting_text: >-
      LMBD1 itself had neither ATPase nor cobalamin transport activities
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19136951
  title: Identification of a putative lysosomal cobalamin exporter altered in the
    cblF defect of vitamin B12 metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding cblF study; identified LMBRD1/LMBD1 as the lysosomal membrane
      protein whose loss causes lysosomal cobalamin accumulation. Establishes
      the core disease/localization link.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput NK-cell membrane proteome; source of the generic
      GO:0016020 membrane HDA. Background-only for LMBRD1 function.
- 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: >-
      SPR/biophysical study showing LMBD1 and ABCD4 (and MMACHC) interact with
      low-nanomolar affinity and proposing vectorial hand-off of lysosomal B12
      to cytosolic MMACHC. Source of the LMBD1-ABCD4 and LMBD1-MMACHC IPIs.
- 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: >-
      Key mechanistic paper: LMBD1 escorts ABCD4 from the ER to the lysosome;
      LMBRD1 knockout mislocalizes ABCD4. Establishes the
      protein-localization-to-lysosome core function.
- 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: >-
      Live-cell FRET confirmation of the selective ABCD4-LMBD1 interaction and
      that ABCD4 lysosomal targeting depends on LMBD1.
- 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: >-
      In vitro reconstitution showing ABCD4 alone transports cobalamin
      (ATP-dependent) and LMBD1 has no cobalamin transport or ATPase activity.
      Directly informs the over-annotation of transporter MF terms to LMBD1.
- 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-9759206
  title: ABCD4:LMBRD1 transports RCbl from lysosomal lumen to cytosol
  findings: []
- id: file:human/LMBRD1/LMBRD1-uniprot.txt
  title: UniProtKB entry Q9NUN5 (LMBD1_HUMAN)
  findings: []
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.