id: P49257
gene_symbol: LMAN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: LMAN1 (Protein ERGIC-53; also Gp58, MR60, lectin mannose-binding 1)
  is a 510-residue type I single-pass transmembrane L-type (leguminous-type) lectin
  of the early secretory pathway. Its luminal carbohydrate-recognition domain binds
  high-mannose N-glycans in a calcium-dependent manner, making it a mannose-specific
  lectin (identical to the myelomonocytic lectin MR60); it is not a glycosidase and
  has no catalytic activity. ERGIC-53 cycles between the endoplasmic reticulum, the
  ER-Golgi intermediate compartment (ERGIC) and the cis-Golgi, exiting the ER in
  COPII-coated vesicles and returning by COPI-dependent retrograde traffic via a
  C-terminal dilysine/diphenylalanine motif. Together with its soluble co-receptor
  MCFD2 it forms an oligomeric cargo receptor (the LMAN1-MCFD2 complex; full-length
  cryo-EM resolves a disulfide-linked homotetramer, revising older homohexamer models)
  that selectively
  captures glycoprotein cargo in the ER and transports it to the Golgi; its best
  characterized cargoes are coagulation factors V and VIII, and additional secretory
  glycoproteins (e.g. alpha-1-antitrypsin, cathepsins) have been proposed. As an
  abundant, rapidly cycling cargo receptor ERGIC-53 also contributes, together with
  Surf4 and p24 family members, to maintaining the architecture of the ERGIC and Golgi
  by controlling COPI recruitment. Loss-of-function mutations in LMAN1 cause autosomal
  recessive combined deficiency of factors V and VIII (F5F8D1).
existing_annotations:
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ERGIC is the defining site of action for ERGIC-53; the phylogenetic annotation
      matches the UniProt subcellular location and the protein's name.
    action: ACCEPT
    reason: Correct core compartment; ERGIC-53 is the canonical ERGIC marker and acts there
      as a cycling cargo receptor.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate'
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ERGIC-53 cycles through the Golgi apparatus membrane as part of its ER-ERGIC-Golgi
      itinerary; consistent with the UniProt Golgi apparatus membrane location.
    action: ACCEPT
    reason: Correct compartment within the cycling itinerary, though the ERGIC is the primary
      steady-state location.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ERGIC-53 captures cargo in the ER and exits via COPII vesicles; ER membrane
      is a bona fide part of its cycling itinerary.
    action: ACCEPT
    reason: Correct compartment; matches the UniProt ER membrane location and the cargo-capture
      step in the ER.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ERGIC-53/MR60 is a mannose-specific lectin; its CRD binds high-mannose N-glycans.
      The F5F8D1 variant W67S abolishes D-mannose binding, directly supporting this molecular
      function.
    action: ACCEPT
    reason: Core molecular function; ERGIC-53 is identical to the mannose-specific lectin MR60
      and recombinant WT (but not W67S) binds D-mannose.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Mannose-specific lectin
    - reference_id: PMID:19787799
      supporting_text: could bind to
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The defining biological process of ERGIC-53 is ER-to-Golgi transport of glycoprotein
      cargo as part of the LMAN1-MCFD2 cargo receptor.
    action: ACCEPT
    reason: Core biological process; well supported across the family and by direct human studies
      of FV/FVIII transport.
    supported_by:
    - reference_id: PMID:12717434
      supporting_text: forms a specific cargo receptor for the ER-to-Golgi transport of selected
- term:
    id: GO:0030134
    label: COPII-coated ER to Golgi transport vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ERGIC-53 is packaged into COPII vesicles at ER exit sites for anterograde transport;
      a C-terminal motif recruits COPII coat components.
    action: ACCEPT
    reason: Correct; ERGIC-53 is a classic COPII cargo/cargo receptor exiting the ER in COPII
      vesicles.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the Golgi apparatus membrane location from the UniProt
      subcellular location vocabulary; consistent with the cycling itinerary.
    action: ACCEPT
    reason: Correct compartment; redundant with the IBA Golgi membrane annotation.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ER membrane location from the UniProt subcellular
      location vocabulary.
    action: ACCEPT
    reason: Correct compartment; redundant with the IBA ER membrane annotation.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Generic ARBA electronic assignment to the endomembrane system; far less informative
      than the specific ERGIC/ER/Golgi compartments already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Overly general parent term; the specific ERGIC membrane, ER membrane and Golgi
      membrane annotations capture the localization precisely.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum-Golgi intermediate
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Bare "membrane" from InterPro; ERGIC-53 is a single-pass type I membrane protein,
      but the term is uninformative relative to the curated ER/ERGIC/Golgi membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; the specific compartment-membrane annotations are
      preferable. ER/ERGIC membrane would be the appropriate refinement.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ERGIC membrane location; this is the precise core
      compartment for ERGIC-53.
    action: ACCEPT
    reason: Correct and specific core compartment; redundant with the IDA ERGIC membrane
      annotation.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16304051
  qualifier: enables
  review:
    summary: IntAct capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22). MCFD2 is the
      soluble co-receptor; the bare protein binding term is uninformative even though the
      interaction is biologically central.
    action: KEEP_AS_NON_CORE
    reason: Records a real, important interaction (MCFD2) but bare GO:0005515 is uninformative;
      the cargo receptor complex (GO:0062137) and D-mannose binding capture the core function.
    supported_by:
    - reference_id: PMID:16304051
      supporting_text: cargo receptor ferrying FV and FVIII from the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17805346
  qualifier: enables
  review:
    summary: IntAct capture of the ERGIC-53/ERp44 interaction (UniProtKB:Q9BS26); ERp44 is a
      thiol-mediated retention protein localized to the ERGIC partly through binding ERGIC-53.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (ERp44) recorded, but bare protein binding is uninformative and
      peripheral to the lectin cargo-receptor core function.
    supported_by:
    - reference_id: PMID:17805346
      supporting_text: interacts with ERGIC-53
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17971482
  qualifier: enables
  review:
    summary: IntAct capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22); deletion of the
      MCFD2 C-terminus impairs binding to ERGIC-53 and causes F5F8D.
    action: KEEP_AS_NON_CORE
    reason: Real MCFD2 interaction, but bare protein binding is uninformative; the cargo
      receptor complex term captures it more meaningfully.
    supported_by:
    - reference_id: PMID:17971482
      supporting_text: ERGIC-53/MCFD2 protein complex functions as transport receptor of
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18287528
  qualifier: enables
  review:
    summary: IntAct capture of the ERGIC-53/Surf4 interaction (UniProtKB:O15260); Surf4 and
      ERGIC-53 are interacting cargo receptors.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (Surf4) recorded, but bare protein binding is uninformative; the
      functional role (Golgi/ERGIC architecture) is captured by GO:0007030.
    supported_by:
    - reference_id: PMID:18287528
      supporting_text: Surf4 was found to interact with
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19787799
  qualifier: enables
  review:
    summary: IntAct capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22); the F5F8D1
      W67S variant abolishes MCFD2 interaction (and D-mannose binding).
    action: KEEP_AS_NON_CORE
    reason: Real MCFD2 interaction, but bare protein binding is uninformative; this paper
      better supports the D-mannose binding annotation.
    supported_by:
    - reference_id: PMID:19787799
      supporting_text: did not co-immunoprecipitate the mutant LMAN1 with MCFD2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20138881
  qualifier: enables
  review:
    summary: IntAct capture from the LMAN1-CRD/MCFD2 crystal structure (UniProtKB:Q8NI22);
      defines the LMAN1-MCFD2 binding interface.
    action: KEEP_AS_NON_CORE
    reason: Real, structurally defined MCFD2 interaction, but bare protein binding is
      uninformative; the cargo receptor complex term captures it.
    supported_by:
    - reference_id: PMID:20138881
      supporting_text: LMAN1 is a glycoprotein receptor, mediating transfer from the ER to
        the ER-Golgi
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20142513
  qualifier: enables
  review:
    summary: IntAct capture from the ERGIC-53-CRD/MCFD2 structural study (UniProtKB:Q8NI22);
      MCFD2 binds a surface remote from the sugar-binding site.
    action: KEEP_AS_NON_CORE
    reason: Real MCFD2 interaction with structural detail, but bare protein binding is
      uninformative as a standalone function.
    supported_by:
    - reference_id: PMID:20142513
      supporting_text: ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput BioPlex interactome capture of the LMAN1-MCFD2 interaction
      (UniProtKB:Q8NI22).
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (MCFD2); bare protein binding is uninformative and
      not elevated to core.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capture of the LMAN1-MCFD2 interaction
      (UniProtKB:Q8NI22).
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (MCFD2); bare protein binding is uninformative and
      not elevated to core.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: cartography of human cellular organization
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined-method electronic assignment to the ERGIC, the core compartment for
      ERGIC-53.
    action: ACCEPT
    reason: Correct core compartment; redundant with IDA/IBA ERGIC annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum-Golgi intermediate
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment to the Golgi apparatus; consistent with the
      cycling itinerary through the Golgi.
    action: ACCEPT
    reason: Correct compartment within the cycling itinerary; ERGIC remains the primary
      steady-state location.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0030017
    label: sarcomere
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment to the sarcomere; there is no biological
      support for ERGIC-53 acting at the sarcomere and it conflicts with its early-secretory-pathway
      localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible compartment for an ER/ERGIC/Golgi cargo receptor; likely spurious
      electronic transfer.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0030134
    label: COPII-coated ER to Golgi transport vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment to the COPII vesicle; ERGIC-53 is a COPII
      cargo receptor.
    action: ACCEPT
    reason: Correct; redundant with the IBA COPII vesicle annotation.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with
      ERGIC-53 capturing cargo in the ER.
    action: ACCEPT
    reason: Correct compartment within the cycling itinerary; supported by direct imaging.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: NAS
  original_reference_id: PMID:36490287
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation; LMAN1 and MCFD2 form a complex that transports FV
      and FVIII from the ER to the Golgi, with MCFD2 carrying the cargo-binding role and LMAN1
      acting as a shuttling carrier.
    action: ACCEPT
    reason: Core biological process; directly asserted by the cited functional study of the
      LMAN1/MCFD2-dependent FV/FVIII secretion pathway.
    supported_by:
    - reference_id: PMID:36490287
      supporting_text: cargo binding and transport are carried out by MCFD2 and that LMAN1
    - reference_id: PMID:36490287
      supporting_text: transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: IDA
  original_reference_id: PMID:12717434
  qualifier: located_in
  review:
    summary: Direct evidence (ComplexPortal) for ERGIC membrane localization; LMAN1 is a
      mannose-binding type 1 transmembrane protein localized to the ERGIC.
    action: ACCEPT
    reason: Correct, specific core compartment with direct support.
    supported_by:
    - reference_id: PMID:12717434
      supporting_text: localized to the endoplasmic
- term:
    id: GO:0062137
    label: cargo receptor complex
  evidence_type: IPI
  original_reference_id: PMID:12717434
  qualifier: part_of
  review:
    summary: The LMAN1-MCFD2 complex (ComplexPortal CPX-8001) is a cargo receptor for ER-to-Golgi
      transport of FV/FVIII; MCFD2 is localized to the ERGIC through a Ca2+-dependent interaction
      with LMAN1.
    action: ACCEPT
    reason: Core cellular component; LMAN1 is a defining subunit of the LMAN1-MCFD2 cargo
      receptor complex.
    supported_by:
    - reference_id: PMID:12717434
      supporting_text: forms a specific cargo receptor for the ER-to-Golgi transport of selected
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34779586
  qualifier: enables
  review:
    summary: IntAct capture of the ERGIC-53/BET1 interaction (UniProtKB:O15155); ERGIC-53 was
      identified as a novel interaction partner of the ER-to-Golgi SNARE BET1.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (BET1) recorded, but bare protein binding is uninformative;
      peripheral to the lectin cargo-receptor core function.
    supported_by:
    - reference_id: PMID:34779586
      supporting_text: ERGIC‐53 as a novel interaction partner of BET1
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: EXP
  original_reference_id: PMID:24498414
  qualifier: enables
  review:
    summary: The CRD coordinates Ca2+, which is required for the lectin's high-mannose
      carbohydrate recognition; structural studies resolve Ca2+ in the sugar-binding pocket.
    action: KEEP_AS_NON_CORE
    reason: Ca2+ is a structural cofactor of the carbohydrate-recognition domain, supporting
      (not equivalent to) the core D-mannose binding function.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: ligand="Ca(2+)"
    - reference_id: PMID:24498414
      supporting_text: carbohydrate recognition domains (CRDs)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31142615
  qualifier: enables
  review:
    summary: IntAct capture of the ERGIC-53/SERPINA1 (alpha-1-antitrypsin) interaction
      (UniProtKB:P01009); alpha-1-antitrypsin is a candidate secretory glycoprotein cargo.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (SERPINA1) recorded; bare protein binding is uninformative, though
      it hints at a broader cargo repertoire.
    supported_by:
    - reference_id: PMID:31142615
      supporting_text: α1-antitrypsin and haptoglobin specifically bind to ERGIC3
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19401338
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization from a study of ER subdomain organization
      (syntaxin 18), consistent with ERGIC-53's cycling itinerary.
    action: ACCEPT
    reason: Correct compartment within the cycling itinerary; supported by direct imaging.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28675934
  qualifier: located_in
  review:
    summary: High-throughput ECM proteomics detection; ERGIC-53 is an intracellular early-secretory-pathway
      membrane protein and not a genuine ECM component.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic over-detection inconsistent with the established ER/ERGIC/Golgi
      localization; not a true ECM protein.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum-Golgi intermediate
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:25037231
  qualifier: located_in
  review:
    summary: High-throughput ECM proteomics detection in colon cancer tissue; not a genuine
      ECM localization for this intracellular cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic over-detection inconsistent with the established intracellular
      localization.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum-Golgi intermediate
- term:
    id: GO:1903748
    label: negative regulation of protein localization to mitochondrion
  evidence_type: HMP
  original_reference_id: PMID:24270810
  qualifier: involved_in
  review:
    summary: LMAN1 was a hit in a genome-wide RNAi screen for regulators of parkin translocation
      to damaged mitochondria; a high-throughput phenotype far removed from its characterized
      cargo-receptor function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput screen hit only; peripheral and not mechanistically connected to
      the core ER-to-Golgi lectin function. Retained but not elevated.
    supported_by:
    - reference_id: PMID:24270810
      supporting_text: regulators that have an impact on parkin
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IDA
  original_reference_id: PMID:21525244
  qualifier: located_in
  review:
    summary: Direct evidence for ERGIC localization from a study of mammalian TRAPP components
      in early ER-to-Golgi trafficking.
    action: ACCEPT
    reason: Correct core compartment with direct support.
    supported_by:
    - reference_id: PMID:21525244
      supporting_text: ER-to-Golgi trafficking at a very early stage
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22337587
  qualifier: enables
  review:
    summary: IPI capture of ERGIC-53 interactions with RAB3GAP1/RAB3GAP2 (Q15042/Q9H2M9) and
      UBXN6 (Q9BZV1) via its C-terminal cytoplasmic tail; the p97-UBXD1 complex modulates
      ERGIC-53 trafficking.
    action: KEEP_AS_NON_CORE
    reason: Real interactions (RAB3GAP1/2, UBXN6) recorded, but bare protein binding is
      uninformative; these modulate ERGIC-53 trafficking and are peripheral to the lectin
      core function.
    supported_by:
    - reference_id: PMID:22337587
      supporting_text: Rab3GAP1/2 complex involved in the fusion of vesicles
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694446
  qualifier: located_in
  review:
    summary: Reactome curation of ERGIC membrane localization in the COPII transport pathway.
    action: ACCEPT
    reason: Correct core compartment; redundant with experimental ERGIC annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-203973
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization during vesicle budding.
    action: ACCEPT
    reason: Correct compartment; redundant with curated ER membrane annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204008
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization during COPII coat recruitment.
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694417
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization during COPII inner-coat assembly.
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694428
  qualifier: located_in
  review:
    summary: Reactome curation (LMAN family proteins bind glycosylated cargo) placing ERGIC-53
      at the ER membrane.
    action: ACCEPT
    reason: Correct compartment; this reaction directly reflects the lectin cargo-binding role.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694431
  qualifier: located_in
  review:
    summary: Reactome curation (hexameric LMAN1:MCFD2 bind glycosylated Factor V and VIII
      precursors) placing ERGIC-53 at the ER membrane.
    action: ACCEPT
    reason: Correct compartment; this reaction directly reflects the FV/FVIII cargo-receptor
      role.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694522
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization during inner coat assembly and cargo
      binding.
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694527
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization during COPII budding (loss of SAR1B
      GTPase).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24806965
  qualifier: enables
  review:
    summary: IPI capture of the ERGIC-53/TMEM115 interaction (UniProtKB:Q12893); TMEM115 is a
      Golgi protein involved in retrograde transport.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (TMEM115) recorded, but bare protein binding is uninformative and
      peripheral to the lectin core function.
    supported_by:
    - reference_id: PMID:24806965
      supporting_text: interacts with the COG complex
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput NK-cell membrane proteome detection; bare "membrane" is
      uninformative relative to the curated ER/ERGIC/Golgi membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term from a proteomics survey; superseded by specific
      compartment-membrane annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: High-throughput exosome proteomics detection (parotid gland exosomes); not a
      site of action for this early-secretory-pathway cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic over-detection; not biologically meaningful for ERGIC-53 function.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum-Golgi intermediate
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-203973
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      during vesicle budding.
    action: ACCEPT
    reason: Correct compartment for a COPII cargo receptor; redundant with COPII vesicle
      annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694409
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      (nucleotide exchange on RAB1).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694418
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      (RAB1 tethering).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694439
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      (COPII binds TRAPPCII and RAB1).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694441
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      (CSNK1D phosphorylates SEC23).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694446
  qualifier: located_in
  review:
    summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane
      (v-SNARE binding on tethered vesicle).
    action: ACCEPT
    reason: Correct compartment; redundant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0012507
    label: ER to Golgi transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-947991
  qualifier: located_in
  review:
    summary: Reactome curation (Transport of glycoproteins with Man8/Man9 N-glycans to the
      Golgi) placing ERGIC-53 in the transport vesicle membrane; directly reflects its
      high-mannose lectin cargo function.
    action: ACCEPT
    reason: Correct compartment; this reaction directly reflects the high-mannose-glycoprotein
      transport role of ERGIC-53.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: proper recognition of COPII coat components
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: IMP
  original_reference_id: PMID:18287528
  qualifier: involved_in
  review:
    summary: Silencing Surf4 together with ERGIC-53 reduces ERGIC clusters and fragments the
      Golgi by impairing COPI recruitment; cargo receptors including ERGIC-53 are required to
      maintain ERGIC/Golgi architecture.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (IMP), but this is an emergent structural role of an
      abundant cycling cargo receptor rather than its primary, defining cargo-transport
      function. Retained as a valid non-core process.
    supported_by:
    - reference_id: PMID:18287528
      supporting_text: cargo receptors are essential for maintaining the architecture of ERGIC
        and Golgi by controlling COP I recruitment
- term:
    id: GO:0034498
    label: early endosome to Golgi transport
  evidence_type: IMP
  original_reference_id: PMID:18287528
  qualifier: involved_in
  negated: true
  review:
    summary: ERGIC-53 functions in the ER-ERGIC-Golgi early secretory pathway and COPI-dependent
      retrograde recycling; the study shows its role is in maintaining ERGIC/Golgi architecture
      via COPI, with no role in early endosome to Golgi transport. The NOT qualifier correctly
      records that ERGIC-53 does NOT act in this endosomal pathway.
    action: ACCEPT
    reason: The negation is appropriate because ERGIC-53 operates in ER/ERGIC/Golgi cargo
      transport and COPI retrograde traffic rather than in endosome-to-Golgi transport.
    supported_by:
    - reference_id: PMID:18287528
      supporting_text: cargo receptors are essential for maintaining the architecture of ERGIC
        and Golgi by controlling COP I recruitment
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IDA
  original_reference_id: PMID:15308636
  qualifier: located_in
  review:
    summary: ERGIC proteomics enriched ERGIC-53 ~110-fold in purified ERGIC membranes,
      providing direct biochemical evidence for ERGIC localization.
    action: ACCEPT
    reason: Correct core compartment with direct biochemical support.
    supported_by:
    - reference_id: PMID:15308636
      supporting_text: enriched 110-fold over the homogenate for ERGIC-53
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9774442
  qualifier: enables
  review:
    summary: IPI capture of an interaction with the oncofetal bile salt-dependent lipase
      (UniProtKB:O75612) from a cloning study; a candidate glycoprotein cargo/partner.
    action: KEEP_AS_NON_CORE
    reason: Real interaction recorded, but bare protein binding is uninformative and the
      partner is peripheral to the established function.
    supported_by:
    - reference_id: PMID:9774442
      supporting_text: oncofetal isoform of the human pancreatic bile
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: TAS
  original_reference_id: PMID:7876089
  qualifier: enables
  review:
    summary: ERGIC-53 is identical to MR60, an intracellular mannose-specific lectin; the TAS
      annotation records the foundational identification of its D-mannose binding activity.
      (PMID:7876089 not cached; supported via the UniProt record documenting ERGIC-53 = MR60.)
    action: ACCEPT
    reason: Core molecular function; ERGIC-53/MR60 is a mannose-specific lectin, corroborated
      by the W67S loss-of-D-mannose-binding variant.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: is identical to MR60, an intracellular mannose-
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: PMID:7876089
  qualifier: located_in
  review:
    summary: TAS annotation of Golgi membrane localization for ERGIC-53; consistent with its
      cycling itinerary through the Golgi. (PMID:7876089 not cached; supported via the UniProt
      record.)
    action: ACCEPT
    reason: Correct compartment within the cycling itinerary; redundant with curated Golgi
      membrane annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: PMID:7876089
  qualifier: located_in
  review:
    summary: TAS annotation of ER membrane localization for ERGIC-53. (PMID:7876089 not cached;
      supported via the UniProt record documenting the ER membrane location.)
    action: ACCEPT
    reason: Correct compartment; redundant with curated ER membrane annotations.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:9546392
  qualifier: involved_in
  review:
    summary: The original F5F8D paper proposed ERGIC-53 may function as a "molecular chaperone"
      for ER-to-Golgi transport of a subset of secreted proteins. ERGIC-53 is a transport
      receptor, not a folding enzyme; the protein folding term reflects the historical
      chaperone framing of its transport role.
    action: KEEP_AS_NON_CORE
    reason: ERGIC-53 is a cargo receptor/lectin, not a folding catalyst; protein folding is at
      best an indirect, downstream consequence of efficient cargo transport. Retained as
      non-core.
    supported_by:
    - reference_id: PMID:9546392
      supporting_text: ERGIC-53 may function as a molecular
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: TAS
  original_reference_id: PMID:9546392
  qualifier: involved_in
  review:
    summary: The foundational F5F8D paper implicates ERGIC-53 in ER-to-Golgi transport of a
      specific subset of secreted proteins including FV and FVIII.
    action: ACCEPT
    reason: Core biological process with strong genetic/biochemical support.
    supported_by:
    - reference_id: PMID:9546392
      supporting_text: transport from ER to Golgi of a specific subset of secreted proteins
- term:
    id: GO:0007596
    label: blood coagulation
  evidence_type: TAS
  original_reference_id: PMID:9546392
  qualifier: involved_in
  review:
    summary: LMAN1 mutations cause combined deficiency of coagulation factors V and VIII;
      blood coagulation is a physiological consequence of its role in secreting FV/FVIII, not
      a direct molecular activity of ERGIC-53.
    action: KEEP_AS_NON_CORE
    reason: Downstream physiological process resulting from cargo transport of FV/FVIII;
      ERGIC-53 itself has no coagulation activity. Retained as non-core.
    supported_by:
    - reference_id: PMID:9546392
      supporting_text: combined deficiency of coagulation factors V and VIII
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:7876089
  qualifier: located_in
  review:
    summary: Legacy TAS "membrane" annotation; bare term is uninformative relative to the
      curated ER/ERGIC/Golgi membrane annotations. (PMID:7876089 not cached; supported via the
      UniProt record.)
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term; superseded by specific compartment-membrane
      annotations. ER/ERGIC membrane is the appropriate refinement.
    supported_by:
    - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
      supporting_text: Single-pass type I membrane protein
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12717434
  title: Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the LMAN1-MCFD2 complex as a cargo receptor for ER-to-Golgi
      transport of FV/FVIII; MCFD2 localized to ERGIC via Ca2+-dependent LMAN1 interaction.
      Source of the cargo receptor complex and ERGIC membrane annotations.
- id: PMID:15308636
  title: Proteomics of endoplasmic reticulum-Golgi intermediate compartment (ERGIC)
    membranes from brefeldin A-treated HepG2 cells identifies ERGIC-32, a new cycling
    protein that interacts with human Erv46.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERGIC proteomics enriched ERGIC-53 ~110-fold; supports ERGIC localization.
      Primary focus is ERGIC-32, but ERGIC-53 is the enrichment marker.
- id: PMID:16304051
  title: Combined deficiency of factor V and factor VIII is due to mutations in either
    LMAN1 or MCFD2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: F5F8D is due to LMAN1 or MCFD2 mutations; the complex is a cargo receptor
      ferrying FV/FVIII from ER to Golgi. Source of an LMAN1-MCFD2 IPI annotation.
- id: PMID:17805346
  title: Sequential steps and checkpoints in the early exocytic compartment during
    secretory IgM biogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERp44 interacts with the hexameric ERGIC-53 lectin; source of the
      ERGIC-53/ERp44 IPI annotation.
- id: PMID:17971482
  title: Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53
    and causes combined factor V and factor VIII deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: ERGIC-53/MCFD2 complex functions as transport receptor of FV/FVIII; MCFD2
      C-terminal deletion impairs binding and causes F5F8D.
- id: PMID:18287528
  title: The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment
    (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Surf4+ERGIC-53 silencing fragments Golgi and reduces ERGIC clusters via
      impaired COPI recruitment; supports Golgi organization (IMP) and the NOT early-endosome-to-Golgi
      negation (ERGIC-53 acts in ER/ERGIC/Golgi, not endosomal traffic). Source of the
      Surf4 IPI.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics; basis for the extracellular exosome
      over-annotation, not a true site of ERGIC-53 action.
- id: PMID:19401338
  title: Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Direct evidence supporting ER localization of ERGIC-53.
- id: PMID:19787799
  title: A novel missense mutation causing abnormal LMAN1 in a Japanese patient with
    combined deficiency of factor V and factor VIII.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: F5F8D1 W67S variant in the CRD abolishes MCFD2 interaction and D-mannose
      binding; recombinant WT LMAN1 binds D-mannose but the mutant does not. Key support for
      the D-mannose binding molecular function.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteomics; basis for the uninformative bare
      "membrane" annotation.
- id: PMID:20138881
  title: Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex provides
    insight into combined deficiency of factor V and factor VIII.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structure of the LMAN1-CRD/MCFD2 complex; LMAN1 is a glycoprotein
      receptor mediating ER-to-ERGIC transfer with co-receptor MCFD2.
- id: PMID:20142513
  title: Structural basis for the cooperative interplay between the two causative
    gene products of combined factor V and factor VIII deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: ERGIC-53-CRD binds MCFD2 at a surface remote from the sugar-binding site,
      independent of sugar binding; forms a 1:1 complex. Defines the cargo receptor interface.
- id: PMID:21525244
  title: C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early
    stage in ER-to-Golgi trafficking.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: TRAPP study; provides direct ERGIC localization evidence for ERGIC-53 in
      early ER-to-Golgi trafficking.
- id: PMID:22337587
  title: Protein interaction profiling of the p97 adaptor UBXD1 points to a role for
    the complex in modulating ERGIC-53 trafficking.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: p97-UBXD1 modulates ERGIC-53 trafficking; ERGIC-53 C-terminal tail interacts
      with RAB3GAP1/2 and UBXN6. Source of these IPI partners.
- id: PMID:24270810
  title: High-content genome-wide RNAi screens identify regulators of parkin upstream
    of mitophagy.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Genome-wide parkin-translocation RNAi screen; LMAN1 is a high-throughput hit
      underlying the negative-regulation-of-protein-localization-to-mitochondrion annotation.
      Peripheral, not mechanistically connected to ERGIC-53's core function.
- id: PMID:24498414
  title: Structural basis for disparate sugar-binding specificities in the homologous
    cargo receptors ERGIC-53 and VIP36.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: ERGIC-53 and VIP36 are L-type lectin cargo receptors; ERGIC-53 has broad,
      lower-affinity high-mannose specificity. Ca2+ in the CRD underpins the metal ion binding
      annotation.
- id: PMID:24806965
  title: TMEM115 is an integral membrane protein of the Golgi complex involved in
    retrograde transport.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: TMEM115 (Golgi, COG-interacting) interacts with ERGIC-53; source of the
      TMEM115 IPI annotation.
- id: PMID:25037231
  title: Extracellular matrix signatures of human primary metastatic colon cancers
    and their metastases to liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput ECM proteomics; basis for the extracellular matrix
      over-annotation, not a true ECM localization.
- id: PMID:28675934
  title: Characterization of the Extracellular Matrix of Normal and Diseased Tissues
    Using Proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput ECM proteomics; basis for the extracellular matrix
      over-annotation.
- id: PMID:31142615
  title: The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of
    secretory proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Primarily about ERGIC3, but documents SERPINA1/alpha-1-antitrypsin as a
      secretory glycoprotein cargo; source of the ERGIC-53/SERPINA1 IPI annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex high-throughput interactome; source of an LMAN1-MCFD2 IPI capture.
- id: PMID:34779586
  title: BET1 variants establish impaired vesicular transport as a cause for muscular
    dystrophy with epilepsy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Identifies ERGIC-53 as a novel interaction partner of the ER-to-Golgi SNARE
      BET1; source of the BET1 IPI annotation.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell endogenous-tagging interactome; source of an LMAN1-MCFD2 IPI
      capture.
- id: PMID:36490287
  title: Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Dissects separable roles; cargo binding/transport are carried out by MCFD2
      with LMAN1 acting as a shuttling carrier; N-glycan binding by LMAN1 is not essential for
      FV/FVIII transport. Supports the ER-to-Golgi transport process annotation.
- id: PMID:36594468
  title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (PMID:36594468, Tang & Ginsburg, J Clin Invest 2023, DOI
      10.1172/jci163838). Authoritative review of ER-to-Golgi cargo receptors framing LMAN1/ERGIC-53
      as a prototypical L-type lectin cargo receptor with a luminal CRD, coiled-coil stalk, TM
      helix, and a cytosolic KKFF motif (FF = ER-exit/COPII determinant; KK = COPI retrieval), and
      noting the cargo repertoire and recognition rules remain incompletely defined. Not cached;
      no supporting_text added. Identified via Falcon deep research.'
- id: PMID:38493152
  title: Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (PMID:38493152, Watanabe et al., Nat Commun 2024, DOI
      10.1038/s41467-024-46747-1). Cryo-EM structure of full-length human ERGIC-53/LMAN1 in
      complex with MCFD2, resolving a homotetrameric assembly (a "four-leaf clover" head with a
      long four-helix-bundle coiled-coil stalk and the TM anchor), revising older hexamer models,
      and proposing regulation of cargo capture/release via stalk bending and metal (Zn2+/Ca2+)
      binding, including an N-terminal Zn2+ site in MCFD2. The top-level description has been
      updated to reflect this homotetramer (revising the older hexamer model). Not cached; no
      supporting_text added. Identified via Falcon deep research.'
- id: PMID:39499573
  title: LMAN1 serves as a cargo receptor for thrombopoietin.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (PMID:39499573, Everett et al., JCI Insight 2024, DOI
      10.1172/jci.insight.175704). Identifies thrombopoietin (TPO) as a new LMAN1-dependent cargo:
      Lman1-/- and hepatocyte-specific Lman1-deletion mice show reduced plasma TPO and
      thrombocytopenia despite unchanged hepatic Tpo mRNA, TPO co-IPs with LMAN1, and this cargo
      relationship is MCFD2-independent (MCFD2 did not co-IP with TPO). Expands the LMAN1 cargo
      repertoire and links LMAN1 to platelet homeostasis. Not cached; no supporting_text added.
      Identified via Falcon deep research.'
- id: PMID:7876089
  title: ERGIC-53, a membrane protein of the endoplasmic reticulum-Golgi intermediate
    compartment, is identical to MR60, an intracellular mannose-specific lectin of
    myelomonocytic cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Not cached in publications/; foundational identification of ERGIC-53 as the
      mannose-specific lectin MR60. Supporting text drawn from the UniProt record, which
      documents this identity and the ER/Golgi membrane localization.
- id: PMID:9546392
  title: Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause
    combined deficiency of coagulation factors V and VIII.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational F5F8D paper; proposes ERGIC-53 as a chaperone/receptor for
      ER-to-Golgi transport of a subset of secreted proteins including FV and FVIII.
- id: PMID:9774442
  title: Molecular cloning of the oncofetal isoform of the human pancreatic bile salt-dependent
    lipase.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cloning study; source of an IPI interaction (bile salt-dependent lipase,
      O75612). Peripheral to ERGIC-53's established function.
- id: Reactome:R-HSA-203973
  title: Vesicle budding
  findings: []
- id: Reactome:R-HSA-204008
  title: SEC31:SEC13 and v-SNARE recruitment
  findings: []
- id: Reactome:R-HSA-5694409
  title: Nucleotide exchange on RAB1
  findings: []
- id: Reactome:R-HSA-5694417
  title: SEC16 complex binds SAR1B:GTP:SEC23:SEC24
  findings: []
- id: Reactome:R-HSA-5694418
  title: RAB1:GTP binds USO1 and GORASP1:GOLGA2
  findings: []
- id: Reactome:R-HSA-5694428
  title: LMAN family proteins bind glycosylated cargo
  findings: []
- id: Reactome:R-HSA-5694431
  title: Hexameric LMAN1:MCFD2 bind glycosylated Factor V and VIII precursors
  findings: []
- id: Reactome:R-HSA-5694439
  title: COPII coat binds TRAPPCII and RAB1:GDP
  findings: []
- id: Reactome:R-HSA-5694441
  title: CSNK1D phosphorylates SEC23
  findings: []
- id: Reactome:R-HSA-5694446
  title: BET1:GOSR2:STX5 bind v-SNARES on tethered vesicle
  findings: []
- id: Reactome:R-HSA-5694522
  title: Inner coat assembly and cargo binding
  findings: []
- id: Reactome:R-HSA-5694527
  title: Loss of SAR1B GTPase
  findings: []
- id: Reactome:R-HSA-947991
  title: Transport of glycoproteins with Man8 (or Man9) N-glycans to the Golgi
  findings: []
- id: file:human/LMAN1/LMAN1-uniprot.txt
  title: UniProt entry P49257 (LMAN1_HUMAN), Protein ERGIC-53
  findings:
  - statement: ERGIC-53 is a mannose-specific L-type lectin (identical to MR60), a single-pass
      type I transmembrane protein of the ERGIC/ER/Golgi membranes; the LMAN1-MCFD2 complex is
      a Ca2+-dependent cargo receptor for ER-to-Golgi transport of selected glycoproteins
      including FV/FVIII; mutations cause F5F8D1.
    reference_section_type: OTHER
core_functions:
- description: Mannose-specific L-type lectin whose luminal carbohydrate-recognition domain
    binds high-mannose N-glycans of glycoprotein cargo in a calcium-dependent manner.
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  locations:
  - id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  supported_by:
  - reference_id: file:human/LMAN1/LMAN1-uniprot.txt
    supporting_text: Mannose-specific lectin
  - reference_id: PMID:24498414
    supporting_text: function as cargo receptors for trafficking certain N-linked glycoproteins
- description: Subunit of the LMAN1-MCFD2 cargo receptor complex that captures glycoprotein
    cargo (notably coagulation factors V and VIII) in the ER and transports it via COPII
    vesicles to the Golgi, cycling back through COPI-dependent retrograde traffic.
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  in_complex:
    id: GO:0062137
    label: cargo receptor complex
  locations:
  - id: GO:0030134
    label: COPII-coated ER to Golgi transport vesicle
  supported_by:
  - reference_id: PMID:12717434
    supporting_text: forms a specific cargo receptor for the ER-to-Golgi transport of selected
  - reference_id: PMID:36490287
    supporting_text: transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi
  directly_involved_in:
  - id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
proposed_new_terms: []
suggested_questions:
- question: Given that LMAN1 N-glycan binding is dispensable for FV/FVIII transport (MCFD2
    carries cargo binding), what is the full repertoire of cargoes that depend on LMAN1's own
    lectin activity versus those routed primarily through MCFD2?
- question: Beyond FV/FVIII, which endogenous high-mannose glycoproteins (e.g. cathepsins,
    alpha-1-antitrypsin) are bona fide LMAN1 cargoes in vivo?
suggested_experiments:
- description: Compare FV/FVIII and broader secretome trafficking in LMAN1-null cells
    reconstituted with wild-type LMAN1 versus the carbohydrate-binding-dead and W67S variants
    to separate the lectin-dependent from MCFD2-shuttling contributions.
- description: Perform proximity labeling (BioID/APEX) from endogenously tagged LMAN1 across
    cell types to define the cargo and machinery interactome and test the proposed cargoes
    (SERPINA1, cathepsins) as genuine clients.