LMAN1

UniProt ID: P49257
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment
IBA
GO_REF:0000033 		ACCEPT
Summary: ERGIC is the defining site of action for ERGIC-53; the phylogenetic annotation matches the UniProt subcellular location and the protein's name.
Reason: Correct core compartment; ERGIC-53 is the canonical ERGIC marker and acts there as a cycling cargo receptor.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
GO:0000139 Golgi membrane
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Correct compartment within the cycling itinerary, though the ERGIC is the primary steady-state location.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Golgi apparatus membrane
GO:0005789 endoplasmic reticulum membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: ERGIC-53 captures cargo in the ER and exits via COPII vesicles; ER membrane is a bona fide part of its cycling itinerary.
Reason: Correct compartment; matches the UniProt ER membrane location and the cargo-capture step in the ER.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005537 D-mannose binding
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Core molecular function; ERGIC-53 is identical to the mannose-specific lectin MR60 and recombinant WT (but not W67S) binds D-mannose.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Mannose-specific lectin
PMID:19787799
could bind to
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport
IBA
GO_REF:0000033 		ACCEPT
Summary: The defining biological process of ERGIC-53 is ER-to-Golgi transport of glycoprotein cargo as part of the LMAN1-MCFD2 cargo receptor.
Reason: Core biological process; well supported across the family and by direct human studies of FV/FVIII transport.
Supporting Evidence:
PMID:12717434
forms a specific cargo receptor for the ER-to-Golgi transport of selected
GO:0030134 COPII-coated ER to Golgi transport vesicle
IBA
GO_REF:0000033 		ACCEPT
Summary: ERGIC-53 is packaged into COPII vesicles at ER exit sites for anterograde transport; a C-terminal motif recruits COPII coat components.
Reason: Correct; ERGIC-53 is a classic COPII cargo/cargo receptor exiting the ER in COPII vesicles.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0000139 Golgi membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of the Golgi apparatus membrane location from the UniProt subcellular location vocabulary; consistent with the cycling itinerary.
Reason: Correct compartment; redundant with the IBA Golgi membrane annotation.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Golgi apparatus membrane
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of the ER membrane location from the UniProt subcellular location vocabulary.
Reason: Correct compartment; redundant with the IBA ER membrane annotation.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0012505 endomembrane system
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: Generic ARBA electronic assignment to the endomembrane system; far less informative than the specific ERGIC/ER/Golgi compartments already annotated.
Reason: Overly general parent term; the specific ERGIC membrane, ER membrane and Golgi membrane annotations capture the localization precisely.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum-Golgi intermediate
GO:0016020 membrane
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
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.
Reason: Uninformative generic term; the specific compartment-membrane annotations are preferable. ER/ERGIC membrane would be the appropriate refinement.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Single-pass type I membrane protein
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of the ERGIC membrane location; this is the precise core compartment for ERGIC-53.
Reason: Correct and specific core compartment; redundant with the IDA ERGIC membrane annotation.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
GO:0005515 protein binding
IPI
PMID:16304051
Combined deficiency of factor V and factor VIII is due to mu... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:16304051
cargo receptor ferrying FV and FVIII from the
GO:0005515 protein binding
IPI
PMID:17805346
Sequential steps and checkpoints in the early exocytic compa... 		KEEP AS NON CORE
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.
Reason: Real interaction (ERp44) recorded, but bare protein binding is uninformative and peripheral to the lectin cargo-receptor core function.
Supporting Evidence:
PMID:17805346
interacts with ERGIC-53
GO:0005515 protein binding
IPI
PMID:17971482
Deletion of 3 residues from the C-terminus of MCFD2 affects ... 		KEEP AS NON CORE
Summary: IntAct capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22); deletion of the MCFD2 C-terminus impairs binding to ERGIC-53 and causes F5F8D.
Reason: Real MCFD2 interaction, but bare protein binding is uninformative; the cargo receptor complex term captures it more meaningfully.
Supporting Evidence:
PMID:17971482
ERGIC-53/MCFD2 protein complex functions as transport receptor of
GO:0005515 protein binding
IPI
PMID:18287528
The cargo receptors Surf4, endoplasmic reticulum-Golgi inter... 		KEEP AS NON CORE
Summary: IntAct capture of the ERGIC-53/Surf4 interaction (UniProtKB:O15260); Surf4 and ERGIC-53 are interacting cargo receptors.
Reason: Real interaction (Surf4) recorded, but bare protein binding is uninformative; the functional role (Golgi/ERGIC architecture) is captured by GO:0007030.
Supporting Evidence:
PMID:18287528
Surf4 was found to interact with
GO:0005515 protein binding
IPI
PMID:19787799
A novel missense mutation causing abnormal LMAN1 in a Japane... 		KEEP AS NON CORE
Summary: IntAct capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22); the F5F8D1 W67S variant abolishes MCFD2 interaction (and D-mannose binding).
Reason: Real MCFD2 interaction, but bare protein binding is uninformative; this paper better supports the D-mannose binding annotation.
Supporting Evidence:
PMID:19787799
did not co-immunoprecipitate the mutant LMAN1 with MCFD2
GO:0005515 protein binding
IPI
PMID:20138881
Crystal structure of the LMAN1-CRD/MCFD2 transport receptor ... 		KEEP AS NON CORE
Summary: IntAct capture from the LMAN1-CRD/MCFD2 crystal structure (UniProtKB:Q8NI22); defines the LMAN1-MCFD2 binding interface.
Reason: Real, structurally defined MCFD2 interaction, but bare protein binding is uninformative; the cargo receptor complex term captures it.
Supporting Evidence:
PMID:20138881
LMAN1 is a glycoprotein receptor, mediating transfer from the ER to the ER-Golgi
GO:0005515 protein binding
IPI
PMID:20142513
Structural basis for the cooperative interplay between the t... 		KEEP AS NON CORE
Summary: IntAct capture from the ERGIC-53-CRD/MCFD2 structural study (UniProtKB:Q8NI22); MCFD2 binds a surface remote from the sugar-binding site.
Reason: Real MCFD2 interaction with structural detail, but bare protein binding is uninformative as a standalone function.
Supporting Evidence:
PMID:20142513
ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: High-throughput BioPlex interactome capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22).
Reason: High-throughput interaction (MCFD2); bare protein binding is uninformative and not elevated to core.
Supporting Evidence:
PMID:33961781
cell-specific remodeling of the human
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		KEEP AS NON CORE
Summary: OpenCell endogenous-tagging interactome capture of the LMAN1-MCFD2 interaction (UniProtKB:Q8NI22).
Reason: High-throughput interaction (MCFD2); bare protein binding is uninformative and not elevated to core.
Supporting Evidence:
PMID:35271311
cartography of human cellular organization
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined-method electronic assignment to the ERGIC, the core compartment for ERGIC-53.
Reason: Correct core compartment; redundant with IDA/IBA ERGIC annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum-Golgi intermediate
GO:0005794 Golgi apparatus
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment to the Golgi apparatus; consistent with the cycling itinerary through the Golgi.
Reason: Correct compartment within the cycling itinerary; ERGIC remains the primary steady-state location.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Golgi apparatus membrane
GO:0030017 sarcomere
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
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.
Reason: Implausible compartment for an ER/ERGIC/Golgi cargo receptor; likely spurious electronic transfer.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Single-pass type I membrane protein
GO:0030134 COPII-coated ER to Golgi transport vesicle
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment to the COPII vesicle; ERGIC-53 is a COPII cargo receptor.
Reason: Correct; redundant with the IBA COPII vesicle annotation.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with ERGIC-53 capturing cargo in the ER.
Reason: Correct compartment within the cycling itinerary; supported by direct imaging.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport
NAS
PMID:36490287
Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking... 		ACCEPT
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.
Reason: Core biological process; directly asserted by the cited functional study of the LMAN1/MCFD2-dependent FV/FVIII secretion pathway.
Supporting Evidence:
PMID:36490287
cargo binding and transport are carried out by MCFD2 and that LMAN1
PMID:36490287
transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane
IDA
PMID:12717434
Bleeding due to disruption of a cargo-specific ER-to-Golgi t... 		ACCEPT
Summary: Direct evidence (ComplexPortal) for ERGIC membrane localization; LMAN1 is a mannose-binding type 1 transmembrane protein localized to the ERGIC.
Reason: Correct, specific core compartment with direct support.
Supporting Evidence:
PMID:12717434
localized to the endoplasmic
GO:0062137 cargo receptor complex
IPI
PMID:12717434
Bleeding due to disruption of a cargo-specific ER-to-Golgi t... 		ACCEPT
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.
Reason: Core cellular component; LMAN1 is a defining subunit of the LMAN1-MCFD2 cargo receptor complex.
Supporting Evidence:
PMID:12717434
forms a specific cargo receptor for the ER-to-Golgi transport of selected
GO:0005515 protein binding
IPI
PMID:34779586
BET1 variants establish impaired vesicular transport as a ca... 		KEEP AS NON CORE
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.
Reason: Real interaction (BET1) recorded, but bare protein binding is uninformative; peripheral to the lectin cargo-receptor core function.
Supporting Evidence:
PMID:34779586
ERGIC‐53 as a novel interaction partner of BET1
GO:0046872 metal ion binding
EXP
PMID:24498414
Structural basis for disparate sugar-binding specificities i... 		KEEP AS NON CORE
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.
Reason: Ca2+ is a structural cofactor of the carbohydrate-recognition domain, supporting (not equivalent to) the core D-mannose binding function.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
ligand="Ca(2+)"
PMID:24498414
carbohydrate recognition domains (CRDs)
GO:0005515 protein binding
IPI
PMID:31142615
The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent tr... 		KEEP AS NON CORE
Summary: IntAct capture of the ERGIC-53/SERPINA1 (alpha-1-antitrypsin) interaction (UniProtKB:P01009); alpha-1-antitrypsin is a candidate secretory glycoprotein cargo.
Reason: Real interaction (SERPINA1) recorded; bare protein binding is uninformative, though it hints at a broader cargo repertoire.
Supporting Evidence:
PMID:31142615
Ξ±1-antitrypsin and haptoglobin specifically bind to ERGIC3
GO:0005783 endoplasmic reticulum
IDA
PMID:19401338
Role of syntaxin 18 in the organization of endoplasmic retic... 		ACCEPT
Summary: Direct evidence for ER localization from a study of ER subdomain organization (syntaxin 18), consistent with ERGIC-53's cycling itinerary.
Reason: Correct compartment within the cycling itinerary; supported by direct imaging.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0031012 extracellular matrix
HDA
PMID:28675934
Characterization of the Extracellular Matrix of Normal and D... 		MARK AS OVER ANNOTATED
Summary: High-throughput ECM proteomics detection; ERGIC-53 is an intracellular early-secretory-pathway membrane protein and not a genuine ECM component.
Reason: Proteomic over-detection inconsistent with the established ER/ERGIC/Golgi localization; not a true ECM protein.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum-Golgi intermediate
GO:0031012 extracellular matrix
HDA
PMID:25037231
Extracellular matrix signatures of human primary metastatic ... 		MARK AS OVER ANNOTATED
Summary: High-throughput ECM proteomics detection in colon cancer tissue; not a genuine ECM localization for this intracellular cargo receptor.
Reason: Proteomic over-detection inconsistent with the established intracellular localization.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum-Golgi intermediate
GO:1903748 negative regulation of protein localization to mitochondrion
HMP
PMID:24270810
High-content genome-wide RNAi screens identify regulators of... 		KEEP AS NON CORE
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.
Reason: High-throughput screen hit only; peripheral and not mechanistically connected to the core ER-to-Golgi lectin function. Retained but not elevated.
Supporting Evidence:
PMID:24270810
regulators that have an impact on parkin
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment
IDA
PMID:21525244
C4orf41 and TTC-15 are mammalian TRAPP components with a rol... 		ACCEPT
Summary: Direct evidence for ERGIC localization from a study of mammalian TRAPP components in early ER-to-Golgi trafficking.
Reason: Correct core compartment with direct support.
Supporting Evidence:
PMID:21525244
ER-to-Golgi trafficking at a very early stage
GO:0005515 protein binding
IPI
PMID:22337587
Protein interaction profiling of the p97 adaptor UBXD1 point... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:22337587
Rab3GAP1/2 complex involved in the fusion of vesicles
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane
TAS
Reactome:R-HSA-5694446 		ACCEPT
Summary: Reactome curation of ERGIC membrane localization in the COPII transport pathway.
Reason: Correct core compartment; redundant with experimental ERGIC annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-203973 		ACCEPT
Summary: Reactome curation of ER membrane localization during vesicle budding.
Reason: Correct compartment; redundant with curated ER membrane annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-204008 		ACCEPT
Summary: Reactome curation of ER membrane localization during COPII coat recruitment.
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-5694417 		ACCEPT
Summary: Reactome curation of ER membrane localization during COPII inner-coat assembly.
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-5694428 		ACCEPT
Summary: Reactome curation (LMAN family proteins bind glycosylated cargo) placing ERGIC-53 at the ER membrane.
Reason: Correct compartment; this reaction directly reflects the lectin cargo-binding role.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-5694431 		ACCEPT
Summary: Reactome curation (hexameric LMAN1:MCFD2 bind glycosylated Factor V and VIII precursors) placing ERGIC-53 at the ER membrane.
Reason: Correct compartment; this reaction directly reflects the FV/FVIII cargo-receptor role.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-5694522 		ACCEPT
Summary: Reactome curation of ER membrane localization during inner coat assembly and cargo binding.
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-5694527 		ACCEPT
Summary: Reactome curation of ER membrane localization during COPII budding (loss of SAR1B GTPase).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0005515 protein binding
IPI
PMID:24806965
TMEM115 is an integral membrane protein of the Golgi complex... 		KEEP AS NON CORE
Summary: IPI capture of the ERGIC-53/TMEM115 interaction (UniProtKB:Q12893); TMEM115 is a Golgi protein involved in retrograde transport.
Reason: Real interaction (TMEM115) recorded, but bare protein binding is uninformative and peripheral to the lectin core function.
Supporting Evidence:
PMID:24806965
interacts with the COG complex
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: High-throughput NK-cell membrane proteome detection; bare "membrane" is uninformative relative to the curated ER/ERGIC/Golgi membrane annotations.
Reason: Uninformative generic term from a proteomics survey; superseded by specific compartment-membrane annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Single-pass type I membrane protein
GO:0070062 extracellular exosome
HDA
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multid... 		MARK AS OVER ANNOTATED
Summary: High-throughput exosome proteomics detection (parotid gland exosomes); not a site of action for this early-secretory-pathway cargo receptor.
Reason: Proteomic over-detection; not biologically meaningful for ERGIC-53 function.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum-Golgi intermediate
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-203973 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane during vesicle budding.
Reason: Correct compartment for a COPII cargo receptor; redundant with COPII vesicle annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-5694409 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane (nucleotide exchange on RAB1).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-5694418 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane (RAB1 tethering).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-5694439 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane (COPII binds TRAPPCII and RAB1).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-5694441 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane (CSNK1D phosphorylates SEC23).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-5694446 		ACCEPT
Summary: Reactome curation placing ERGIC-53 in the ER-to-Golgi transport vesicle membrane (v-SNARE binding on tethered vesicle).
Reason: Correct compartment; redundant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0012507 ER to Golgi transport vesicle membrane
TAS
Reactome:R-HSA-947991 		ACCEPT
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.
Reason: Correct compartment; this reaction directly reflects the high-mannose-glycoprotein transport role of ERGIC-53.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
proper recognition of COPII coat components
GO:0007030 Golgi organization
IMP
PMID:18287528
The cargo receptors Surf4, endoplasmic reticulum-Golgi inter... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:18287528
cargo receptors are essential for maintaining the architecture of ERGIC and Golgi by controlling COP I recruitment
GO:0034498 early endosome to Golgi transport
IMP NOT
PMID:18287528
The cargo receptors Surf4, endoplasmic reticulum-Golgi inter... 		ACCEPT
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.
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.
Supporting Evidence:
PMID:18287528
cargo receptors are essential for maintaining the architecture of ERGIC and Golgi by controlling COP I recruitment
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment
IDA
PMID:15308636
Proteomics of endoplasmic reticulum-Golgi intermediate compa... 		ACCEPT
Summary: ERGIC proteomics enriched ERGIC-53 ~110-fold in purified ERGIC membranes, providing direct biochemical evidence for ERGIC localization.
Reason: Correct core compartment with direct biochemical support.
Supporting Evidence:
PMID:15308636
enriched 110-fold over the homogenate for ERGIC-53
GO:0005515 protein binding
IPI
PMID:9774442
Molecular cloning of the oncofetal isoform of the human panc... 		KEEP AS NON CORE
Summary: IPI capture of an interaction with the oncofetal bile salt-dependent lipase (UniProtKB:O75612) from a cloning study; a candidate glycoprotein cargo/partner.
Reason: Real interaction recorded, but bare protein binding is uninformative and the partner is peripheral to the established function.
Supporting Evidence:
PMID:9774442
oncofetal isoform of the human pancreatic bile
GO:0005537 D-mannose binding
TAS
PMID:7876089
ERGIC-53, a membrane protein of the endoplasmic reticulum-Go... 		ACCEPT
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.)
Reason: Core molecular function; ERGIC-53/MR60 is a mannose-specific lectin, corroborated by the W67S loss-of-D-mannose-binding variant.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
is identical to MR60, an intracellular mannose-
GO:0000139 Golgi membrane
TAS
PMID:7876089
ERGIC-53, a membrane protein of the endoplasmic reticulum-Go... 		ACCEPT
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.)
Reason: Correct compartment within the cycling itinerary; redundant with curated Golgi membrane annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Golgi apparatus membrane
GO:0005789 endoplasmic reticulum membrane
TAS
PMID:7876089
ERGIC-53, a membrane protein of the endoplasmic reticulum-Go... 		ACCEPT
Summary: TAS annotation of ER membrane localization for ERGIC-53. (PMID:7876089 not cached; supported via the UniProt record documenting the ER membrane location.)
Reason: Correct compartment; redundant with curated ER membrane annotations.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Endoplasmic reticulum
GO:0006457 protein folding
TAS
PMID:9546392
Mutations in the ER-Golgi intermediate compartment protein E... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:9546392
ERGIC-53 may function as a molecular
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport
TAS
PMID:9546392
Mutations in the ER-Golgi intermediate compartment protein E... 		ACCEPT
Summary: The foundational F5F8D paper implicates ERGIC-53 in ER-to-Golgi transport of a specific subset of secreted proteins including FV and FVIII.
Reason: Core biological process with strong genetic/biochemical support.
Supporting Evidence:
PMID:9546392
transport from ER to Golgi of a specific subset of secreted proteins
GO:0007596 blood coagulation
TAS
PMID:9546392
Mutations in the ER-Golgi intermediate compartment protein E... 		KEEP AS NON CORE
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.
Reason: Downstream physiological process resulting from cargo transport of FV/FVIII; ERGIC-53 itself has no coagulation activity. Retained as non-core.
Supporting Evidence:
PMID:9546392
combined deficiency of coagulation factors V and VIII
GO:0016020 membrane
TAS
PMID:7876089
ERGIC-53, a membrane protein of the endoplasmic reticulum-Go... 		MARK AS OVER ANNOTATED
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.)
Reason: Uninformative generic term; superseded by specific compartment-membrane annotations. ER/ERGIC membrane is the appropriate refinement.
Supporting Evidence:
file:human/LMAN1/LMAN1-uniprot.txt
Single-pass type I membrane protein

Core Functions

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:
D-mannose binding
Cellular Locations:
endoplasmic reticulum-Golgi intermediate compartment
Supporting Evidence:
  • file:human/LMAN1/LMAN1-uniprot.txt
    Mannose-specific lectin
  • PMID:24498414
    function as cargo receptors for trafficking certain N-linked glycoproteins

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:
D-mannose binding
Directly Involved In:
endoplasmic reticulum to Golgi vesicle-mediated transport
Cellular Locations:
COPII-coated ER to Golgi transport vesicle
In Complex:
cargo receptor complex
Supporting Evidence:
  • PMID:12717434
    forms a specific cargo receptor for the ER-to-Golgi transport of selected
  • PMID:36490287
    transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:12717434
Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex.
PMID:15308636
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.
PMID:16304051
Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2.
PMID:17805346
Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis.
PMID:17971482
Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency.
PMID:18287528
The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi.
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
PMID:19401338
Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains.
PMID:19787799
A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20138881
Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex provides insight into combined deficiency of factor V and factor VIII.
PMID:20142513
Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency.
PMID:21525244
C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking.
PMID:22337587
Protein interaction profiling of the p97 adaptor UBXD1 points to a role for the complex in modulating ERGIC-53 trafficking.
PMID:24270810
High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy.
PMID:24498414
Structural basis for disparate sugar-binding specificities in the homologous cargo receptors ERGIC-53 and VIP36.
PMID:24806965
TMEM115 is an integral membrane protein of the Golgi complex involved in retrograde transport.
PMID:25037231
Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.
PMID:28675934
Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.
PMID:31142615
The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34779586
BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:36490287
Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII.
PMID:36594468
Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
PMID:38493152
Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport.
PMID:39499573
LMAN1 serves as a cargo receptor for thrombopoietin.
PMID:7876089
ERGIC-53, a membrane protein of the endoplasmic reticulum-Golgi intermediate compartment, is identical to MR60, an intracellular mannose-specific lectin of myelomonocytic cells.
PMID:9546392
Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII.
PMID:9774442
Molecular cloning of the oncofetal isoform of the human pancreatic bile salt-dependent lipase.
Reactome:R-HSA-203973
Vesicle budding
Reactome:R-HSA-204008
SEC31:SEC13 and v-SNARE recruitment
Reactome:R-HSA-5694409
Nucleotide exchange on RAB1
Reactome:R-HSA-5694417
SEC16 complex binds SAR1B:GTP:SEC23:SEC24
Reactome:R-HSA-5694418
RAB1:GTP binds USO1 and GORASP1:GOLGA2
Reactome:R-HSA-5694428
LMAN family proteins bind glycosylated cargo
Reactome:R-HSA-5694431
Hexameric LMAN1:MCFD2 bind glycosylated Factor V and VIII precursors
Reactome:R-HSA-5694439
COPII coat binds TRAPPCII and RAB1:GDP
Reactome:R-HSA-5694441
CSNK1D phosphorylates SEC23
Reactome:R-HSA-5694446
BET1:GOSR2:STX5 bind v-SNARES on tethered vesicle
Reactome:R-HSA-5694522
Inner coat assembly and cargo binding
Reactome:R-HSA-5694527
Loss of SAR1B GTPase
Reactome:R-HSA-947991
Transport of glycoproteins with Man8 (or Man9) N-glycans to the Golgi
file:human/LMAN1/LMAN1-uniprot.txt
UniProt entry P49257 (LMAN1_HUMAN), Protein ERGIC-53
  • 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.

Suggested Questions for Experts

Q: 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?

Q: Beyond FV/FVIII, which endogenous high-mannose glycoproteins (e.g. cathepsins, alpha-1-antitrypsin) are bona fide LMAN1 cargoes in vivo?

Suggested Experiments

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(LMAN1-deep-research-falcon.md)
Research Report: Human **LMAN1 (ERGIC-53)** Functional Annotation (UniProt **P49257**) Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-12T03:53:50.250092
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000028 The full-length cryo-EM architecture of the ERGIC-53/LMAN1 tetramer in complex with MCFD2 is shown in Figure 2b and 2c (image-003), (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human LMAN1 (ERGIC-53) Functional Annotation (UniProt P49257)

0) Target identity verification (critical)

The UniProt accession P49257 corresponds to human LMAN1, whose protein product is also known as ERGIC-53/p58/Gp58 and functions as a type I transmembrane L-type lectin cargo receptor in the early secretory pathway (ERβ†’ERGICβ†’Golgi). This identity is consistent with (i) a luminal carbohydrate-recognition domain (CRD) that binds mannose/high-mannose glycans in a Ca2+-dependent manner, (ii) a long luminal coiled-coil stalk, (iii) a single-pass transmembrane helix, and (iv) a short cytosolic tail with a C-terminal KKFF trafficking motif required for ER–Golgi cycling. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7)

1) Key concepts and definitions (current understanding)

1.1 LMAN1/ERGIC-53 as a cargo receptor

In mammalian cells, cargo receptors are transmembrane proteins that facilitate recruitment of selected luminal cargo into COPII carriers at ER exit sites, accelerating ER-to-Golgi transport compared with bulk flow. LMAN1/ERGIC-53 is a prototypical mammalian cargo receptor: it captures subsets of newly synthesized secretory and membrane proteins in the ER and promotes their export to the Golgi apparatus. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7)

1.2 Domain architecture and topology

LMAN1 is a type I transmembrane protein with an N-terminal luminal L-type lectin CRD (carbohydrate-recognition domain) and a long luminal stalk (coiled-coils), followed by a transmembrane helix and a short cytosolic tail. The cytosolic tail contains the KKFF motif that supports cycling between ER/ERGIC/Golgi. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7, watanabe2024structureoffulllength media cf25ea0c)

1.3 The LMAN1–MCFD2 cargo receptor complex

LMAN1 forms a functional complex with MCFD2, a small soluble EF-hand protein that binds Ca2+. The complex is Ca2+-dependent and is central to ER export of canonical cargos such as coagulation factors V and VIII. (zhang2023separaterolesof pages 1-2, tang2023cargoselectionin pages 5-7)

2) Molecular function and mechanism

2.1 Lectin (glycan) recognition and its limits

LMAN1’s luminal CRD binds mannose/high-mannose glycans in a Ca2+-dependent manner and contributes to selective trafficking of certain glycoprotein cargos. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7)

However, lectin binding is not universally required for all LMAN1-dependent cargos: in a mechanistic cell system, carbohydrate-binding mutants of LMAN1 retained the ability to rescue much of FVIII secretion, supporting at least partial lectin-independent cargo recognition (protein–protein interactions) for some cargos. (zhang2023separaterolesof pages 8-9)

2.2 New structural mechanism (2024): full-length ERGIC-53/LMAN1–MCFD2 architecture

A major 2024 advance is the cryo-EM structure of full-length human ERGIC-53 (LMAN1) in complex with MCFD2, revealing:
- A homotetrameric assembly (revising older hexamer models), with a β€œfour-leaf clover-like” head region and a long stalk built from multiple four-helix coiled-coils leading to the transmembrane anchor. (watanabe2024structureoffulllength pages 1-2)
- Proposed regulation of cargo capture/release via stalk bending and metal binding, including an N-terminal Zn2+-binding site in MCFD2 that may modulate cargo binding. (watanabe2024structureoffulllength pages 1-2)

The corresponding figure panels provide a compact visual summary of the tetrameric architecture and domain organization (head/stalk/TM/tail). (watanabe2024structureoffulllength media cf25ea0c, watanabe2024structureoffulllength media 7e4fa169)

2.3 Partner function partitioning (2023): β€œseparate roles” model

A 2023 mechanistic study supports a model in which MCFD2 is the primary interacting partner for FV/FVIII cargo, while LMAN1 primarily serves as the shuttling membrane carrier of MCFD2 within the ER–ERGIC cycling route. (zhang2023separaterolesof pages 1-2, zhang2023separaterolesof pages 8-9)

3) Subcellular localization and pathway context

3.1 Where LMAN1 acts in the cell

LMAN1/ERGIC-53 is primarily localized to the ER and ERGIC, and cycles through the ER β†’ ERGIC β†’ cis-Golgi compartments as part of early secretory trafficking. (tang2023cargoselectionin pages 5-7, tang2023cargoselectionin pages 9-10, watanabe2024structureoffulllength pages 1-2)

3.2 Trafficking signals and coat usage (COPII export and COPI retrieval)

The KKFF motif in the cytosolic tail is functionally subdivided:
- FF acts as an ER exit determinant that promotes export (consistent with COPII-mediated trafficking from ER exit sites).
- KK mediates COPI-dependent retrieval to the ER, enabling receptor recycling. (tang2023cargoselectionin pages 5-7)

Oligomerization is an important determinant for sorting into COPII-coated carriers (notably dimerization is described as required for efficient exit in the review context, while the full-length structure resolves tetrameric architecture). (tang2023cargoselectionin pages 5-7, watanabe2024structureoffulllength pages 1-2)

4) Cargo repertoire (substrate specificity = transported cargos)

4.1 Canonical cargos: coagulation factor V (FV) and factor VIII (FVIII)

The best-established physiological role for LMAN1 is facilitating ER-to-Golgi trafficking of FV and FVIII, via the LMAN1–MCFD2 complex. Loss-of-function variants in LMAN1 or MCFD2 cause the autosomal recessive bleeding disorder combined deficiency of FV and FVIII (F5F8D) due to impaired secretion/transport of both factors. (tang2023cargoselectionin pages 5-7, zhang2023separaterolesof pages 1-2)

4.2 Additional cargos supported in recent literature

Recent sources and cited evidence support an expanding (but still limited) cargo list including:
- Ξ±1-antitrypsin (A1AT), with experimental evidence of reduced secretion in LMAN1-deficient contexts and review-level synthesis that A1AT export requires both LMAN1 and MCFD2. (zhang2023separaterolesof pages 8-9, everett2024lman1servesas pages 6-7)
- Thrombopoietin (TPO) (new 2024 primary discovery): LMAN1 is required for efficient TPO secretion from hepatocytes, and this appears to be MCFD2-independent. (everett2024lman1servesas pages 1-2, everett2024lman1servesas pages 4-6)
- Review-level summary indicates some cargos are glycan-binding dependent (e.g., CTSC/CTSZ/A1AT/Mac-2BP/MMP-9), while FVIII and some neuroreceptors may not require carbohydrate binding. (tang2023cargoselectionin pages 5-7)

4.3 Expert assessment: cargo specificity remains an open problem

A 2023 expert review emphasizes that, despite LMAN1 being a prototypical cargo receptor, the recognition motif(s) and determinants for many LMAN1/MCFD2-dependent cargos remain unclear, and the full cargo spectrum is still incompletely defined. (tang2023cargoselectionin pages 5-7, tang2023cargoselectionin pages 7-8)

5) Disease relevance and real-world implementations

5.1 Genetic disease: combined factor V and VIII deficiency (F5F8D)

Etiology and genetics. F5F8D is caused by loss-of-function variants in LMAN1 (~70% of cases) or MCFD2 (~30%), disrupting ER-to-Golgi trafficking of FV and FVIII rather than directly mutating F5 or F8. (tang2023cargoselectionin pages 5-7, zhang2023separaterolesof pages 1-2)

Epidemiology. F5F8D is rare, with an estimated prevalence around 1:1,000,000 in the general population (higher in consanguineous populations). (yakovleva2024hereditarycombineddeficiency pages 1-3)

Clinical phenotype and statistics (2024 case series). In a 2024 Russian series (n=6), mean FV activity was 5.7%, mean FVIII activity 9.0%, mean aPTT 85 s, and bleeding severity (ISTH-BAT) ranged 17–29 (mean 23.5). (yakovleva2024hereditarycombineddeficiency pages 1-3)

Diagnostic implementation. Clinical evaluation and genetic confirmation (LMAN1/MCFD2) are used to establish diagnosis and inform counseling; 2024 work illustrates family sequencing approaches (e.g., Sanger sequencing for causal variants) integrated with coagulation assays (PT/aPTT and FV/FVIII activity). (ma2024rnaitargetinglman1mcfd2 pages 3-5)

5.2 New physiological implication (2024): platelet biology via TPO secretion

A 2024 primary study links LMAN1 to platelet homeostasis via TPO secretion. In Lman1–/– mice, plasma TPO was reduced (about 230Γ—10^3 pg/mL β†’ 120Γ—10^3 pg/mL, ELISA; P<0.0024) despite unchanged hepatic Tpo mRNA, consistent with a secretion defect. Hepatocyte-specific Lman1 deletion caused thrombocytopenia, and TPO physically interacted with LMAN1 by co-IP, while MCFD2 did not co-IP with TPOβ€”supporting an MCFD2-independent LMAN1 cargo relationship. (everett2024lman1servesas pages 4-6)

5.3 Emerging translational concept (2024): targeting LMAN1/MCFD2 for anticoagulation

A 2024 preclinical study explored GalNAc-conjugated siRNA knockdown of LMAN1/MCFD2 in mouse liver as an anticoagulation strategy. A single 3 mg/kg dose reduced hepatic LMAN1 mRNA to ~19.97%Β±3.78% and MCFD2 mRNA to ~32.22%Β±13.14% at 7 days; protein levels dropped to ~30% (LMAN1) and ~50% (MCFD2) of control in liver. Functional effects included APTT prolongation and reduced FVIII activity, with tail-bleeding generally not significantly increased in this model. (ma2024rnaitargetinglman1mcfd2 pages 1-3, ma2024rnaitargetinglman1mcfd2 pages 9-10, ma2024rnaitargetinglman1mcfd2 pages 10-12)

6) Recent developments (2023–2024 highlights)

  1. Structural resolution of full-length complex (2024): cryo-EM structures revised ERGIC-53/LMAN1 oligomeric state to a homotetramer and proposed new mechanistic elements (stalk flexibility; Zn2+ regulation in MCFD2) for cargo capture/release. (Watanabe et al., 2024-03; https://doi.org/10.1038/s41467-024-46747-1) (watanabe2024structureoffulllength pages 1-2)
  2. Expanded cargo repertoire (2024): thrombopoietin identified as an LMAN1-dependent, MCFD2-independent cargo, connecting LMAN1 to platelet biology. (Everett et al., 2024-12; https://doi.org/10.1172/jci.insight.175704) (everett2024lman1servesas pages 1-2, everett2024lman1servesas pages 4-6)
  3. Mechanistic partitioning (2023): evidence supporting distinct roles for LMAN1 vs MCFD2 in FV/FVIII transport, including lectin-independent aspects for FVIII secretion. (Zhang et al., 2023-03; https://doi.org/10.1182/bloodadvances.2022008788) (zhang2023separaterolesof pages 1-2, zhang2023separaterolesof pages 8-9)
  4. Therapeutic targeting concept (2024): proof-of-concept liver-directed RNAi inhibition of LMAN1/MCFD2 decreases FVIII and prolongs clotting time in mice. (Ma et al., 2024-09; https://doi.org/10.1007/s11239-024-03034-6) (ma2024rnaitargetinglman1mcfd2 pages 1-3, ma2024rnaitargetinglman1mcfd2 pages 9-10)

7) Consolidated quick-reference table

The following table summarizes the core functional annotation elements, evidence types, and quantitative highlights.

Concept/Entity Current understanding Evidence type Key quantitative/statistical data if available Primary recent source(s) with year
Protein type / topology Human LMAN1 (ERGIC-53; UniProt P49257) is a type I transmembrane L-type lectin cargo receptor of the early secretory pathway. It has an N-terminal luminal carbohydrate-recognition domain (CRD), a long luminal stalk, a single-pass TM helix, and a short cytosolic tail carrying trafficking motifs including KKFF for ER/Golgi cycling. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7) Cryo-EM, structural analysis, review Cytosolic tail is described as 12 residues in the 2023 review; full-length structure is ~340 Γ… long in cryo-EM figures. (tang2023cargoselectionin pages 5-7, watanabe2024structureoffulllength media cf25ea0c) Watanabe et al., 2024; Tang & Ginsburg, 2023
Lectin domain / glycan recognition The luminal CRD binds mannose/high-mannose glycans in a Ca2+-dependent manner and contributes to selective recruitment of glycoprotein cargo. Some cargos appear glycan-dependent, whereas others can be recognized through lectin-independent protein interactions. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7, zhang2023separaterolesof pages 8-9) Cryo-EM, prior structural/biochemical evidence summarized in review, rescue assays No single universal cargo motif has been defined; carbohydrate-binding mutants can still rescue much of FVIII secretion in KO cells, supporting partial lectin-independent recognition. (zhang2023separaterolesof pages 8-9) Watanabe et al., 2024; Tang & Ginsburg, 2023; Zhang et al., 2023
Oligomerization A major 2024 advance is that full-length ERGIC-53 was resolved as a homotetramer with a four-leaf-clover head and long flexible coiled-coil stalk, revising older hexamer models. Oligomerization is functionally linked to early secretory pathway trafficking. (watanabe2024structureoffulllength pages 1-2) Cryo-EM, review Cryo-EM consensus map at 3.51 Γ…; head substates at ~3.3–3.4 Γ…. (watanabe2024structureoffulllength pages 11-12) Watanabe et al., 2024
Binding partner MCFD2 MCFD2 is a soluble EF-hand protein that forms a Ca2+-dependent 1:1 complex with LMAN1 and is required for efficient export of canonical cargos such as FV and FVIII. Recent structural work also indicates an N-terminal Zn2+-binding site in MCFD2 that may regulate cargo binding/release. (zhang2023separaterolesof pages 1-2, watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7) Cryo-EM, structural analysis, review F5F8D genetics are attributed to LMAN1 in ~70% of cases and MCFD2 in ~30% of cases. (tang2023cargoselectionin pages 5-7, zhang2023separaterolesof pages 1-2) Watanabe et al., 2024; Tang & Ginsburg, 2023; Zhang et al., 2023
Localization / trafficking cycle LMAN1 cycles between the ER, ER-Golgi intermediate compartment (ERGIC), and Golgi/cis-Golgi, acting as a cargo receptor that helps recruit selected clients into COPII-mediated ER export and then recycles back through retrieval signals. (watanabe2024structureoffulllength pages 1-2, watanabe2024structureoffulllength pages 12-13, tang2023cargoselectionin pages 9-10) Cryo-EM-informed structural analysis, review Not quantified directly in the extracted evidence; pathway placement is consistent across review and structural sources. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 9-10) Watanabe et al., 2024; Tang & Ginsburg, 2023
Canonical cargos: factor V and factor VIII The best-established physiological role of the LMAN1-MCFD2 complex is ER-to-Golgi transport of coagulation factors V and VIII. Recent mechanistic work suggests MCFD2 is likely the primary interacting partner for FV/FVIII cargo, while LMAN1 mainly serves as the shuttling membrane carrier. (zhang2023separaterolesof pages 1-2, zhang2023separaterolesof pages 8-9) Knockout/complementation, secretion assays, review In human F5F8D, FV and FVIII are typically reduced to ~5%–30% of normal; some summaries cite average levels around 9%–15%. (ma2024rnaitargetinglman1mcfd2 pages 1-3, ma2024rnaitargetinglman1mcfd2 pages 10-12, zhang2023separaterolesof pages 1-2) Zhang et al., 2023; Ma et al., 2024
Additional cargos Beyond FV/FVIII, evidence supports LMAN1-dependent trafficking of Ξ±1-antitrypsin (A1AT), Mac-2BP, MMP-9, and now thrombopoietin (TPO). A1AT appears to require both LMAN1 and MCFD2, whereas TPO is the first reported LMAN1-dependent cargo that is MCFD2-independent. (zhang2023separaterolesof pages 10-11, everett2024lman1servesas pages 4-6, watanabe2024structureoffulllength pages 11-12, everett2024lman1servesas pages 6-7, everett2024lman1servesas pages 1-2) Knockout mice, hepatocyte-specific deletion, co-IP, secretion assays, review In Lman1-deficient mice, plasma TPO fell from about 230 Γ— 10^3 to 120 Γ— 10^3 pg/mL; hepatocyte-specific loss caused significant thrombocytopenia. (everett2024lman1servesas pages 4-6) Everett et al., 2024; Zhang et al., 2023; Watanabe et al., 2024
Disease association: F5F8D Biallelic loss-of-function variants in LMAN1 cause combined deficiency of coagulation factors V and VIII (F5F8D), a rare autosomal recessive bleeding disorder due to impaired cargo export rather than defects in F5 or F8 genes themselves. (tang2023cargoselectionin pages 5-7, yakovleva2024hereditarycombineddeficiency pages 1-3, zhang2023separaterolesof pages 1-2) Human genetics, clinical case series, review Prevalence is about 1:1,000,000 overall, but can be much higher in some consanguineous populations; a 2024 Russian series of 6 patients reported mean FV 5.7%, FVIII 9.0%, aPTT 85 s, and mean ISTH-BAT 23.5. (yakovleva2024hereditarycombineddeficiency pages 1-3, zhang2023separaterolesof pages 1-2) Yakovleva et al., 2024; Tang & Ginsburg, 2023; Zhang et al., 2023
Emerging therapeutic targeting Experimental liver-directed GalNAc-siRNA knockdown of LMAN1 or MCFD2 reduces FVIII and prolongs coagulation times in mice, suggesting partial inhibition of the complex could be explored as an anticoagulation strategy. (ma2024rnaitargetinglman1mcfd2 pages 10-12, ma2024rnaitargetinglman1mcfd2 pages 9-10, ma2024rnaitargetinglman1mcfd2 pages 1-3) Preclinical RNAi, RT-qPCR, western blot, coagulation assays After a single 3 mg/kg dose, hepatic LMAN1 mRNA fell to 19.97% Β± 3.78% and MCFD2 mRNA to 32.22% Β± 13.14%; liver LMAN1 and MCFD2 proteins fell to ~30% and ~50% of control, respectively. APTT peaked around day 13, and tail bleeding was generally not significantly increased. (ma2024rnaitargetinglman1mcfd2 pages 9-10, ma2024rnaitargetinglman1mcfd2 pages 1-3) Ma et al., 2024
Open mechanistic questions Expert reviews emphasize that the full cargo repertoire remains limited and incompletely defined, the recognition motifs for many cargos are still unclear, and secretion may involve backup receptors or bulk-flow pathways. Recent structure work clarifies architecture but not all determinants of cargo specificity or in vivo release dynamics. (watanabe2024structureoffulllength pages 1-2, tang2023cargoselectionin pages 5-7, tang2023cargoselectionin pages 7-8) Review, cryo-EM primary study No definitive quantitative estimate of total cargo repertoire is available in the extracted evidence. (tang2023cargoselectionin pages 5-7, tang2023cargoselectionin pages 7-8) Tang & Ginsburg, 2023; Watanabe et al., 2024

Table: This table compiles compact, evidence-backed functional annotation points for human LMAN1/ERGIC-53, emphasizing mechanism, trafficking, cargo specificity, disease relevance, and recent 2023–2024 advances. It is useful as a quick reference for integrating structural, cell-biological, and clinical findings.

8) Limitations and remaining knowledge gaps (from expert reviews)

Despite extensive study of ER export, experts emphasize that only a small fraction of secreted proteins have known cargo receptors; for LMAN1 specifically, the complete cargo repertoire and generalizable cargo recognition rules remain incompletely defined, and secretion may rely on bulk flow and/or backup receptors for many proteins. (tang2023cargoselectionin pages 7-8, tang2023cargoselectionin pages 5-7)

Key sources (with dates and URLs)

  • Watanabe S. et al. β€œStructure of full-length ERGIC-53 in complex with MCFD2 for cargo transport”. Nature Communications. 2024-03. https://doi.org/10.1038/s41467-024-46747-1 (watanabe2024structureoffulllength pages 1-2)
  • Tang V.T., Ginsburg D. β€œCargo selection in endoplasmic reticulum–to–Golgi transport and relevant diseases”. Journal of Clinical Investigation. 2023-01. https://doi.org/10.1172/jci163838 (tang2023cargoselectionin pages 5-7)
  • Zhang Y. et al. β€œSeparate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII”. Blood Advances. 2023-03. https://doi.org/10.1182/bloodadvances.2022008788 (zhang2023separaterolesof pages 1-2)
  • Everett L.A. et al. β€œLMAN1 serves as a cargo receptor for thrombopoietin”. JCI Insight. 2024-12. https://doi.org/10.1172/jci.insight.175704 (everett2024lman1servesas pages 1-2)
  • Ma S. et al. β€œRNAi targeting LMAN1-MCFD2 complex promotes anticoagulation in mice”. Journal of Thrombosis and Thrombolysis. 2024-09. https://doi.org/10.1007/s11239-024-03034-6 (ma2024rnaitargetinglman1mcfd2 pages 1-3)
  • Yakovleva E.V. et al. β€œHereditary combined deficiency of factors V and VIII: observations in the Russian population”. Russian Journal of Hematology and Transfusiology. 2024-11. https://doi.org/10.35754/0234-5730-2024-69-3-344-355 (yakovleva2024hereditarycombineddeficiency pages 1-3)

References

  1. (watanabe2024structureoffulllength pages 1-2): Satoshi Watanabe, Yoshiaki Kise, Kento Yonezawa, Mariko Inoue, Nobutaka Shimizu, Osamu Nureki, and Kenji Inaba. Structure of full-length ergic-53 in complex with mcfd2 for cargo transport. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46747-1, doi:10.1038/s41467-024-46747-1. This article has 14 citations and is from a highest quality peer-reviewed journal.

  2. (tang2023cargoselectionin pages 5-7): Vi T. Tang and David Ginsburg. Cargo selection in endoplasmic reticulum–to–golgi transport and relevant diseases. The Journal of Clinical Investigation, Jan 2023. URL: https://doi.org/10.1172/jci163838, doi:10.1172/jci163838. This article has 60 citations.

  3. (watanabe2024structureoffulllength media cf25ea0c): Satoshi Watanabe, Yoshiaki Kise, Kento Yonezawa, Mariko Inoue, Nobutaka Shimizu, Osamu Nureki, and Kenji Inaba. Structure of full-length ergic-53 in complex with mcfd2 for cargo transport. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46747-1, doi:10.1038/s41467-024-46747-1. This article has 14 citations and is from a highest quality peer-reviewed journal.

  4. (zhang2023separaterolesof pages 1-2): Yuanbao Zhang, Zhigang Liu, and Bin Zhang. Separate roles of lman1 and mcfd2 in er-to-golgi trafficking of fv and fviii. Mar 2023. URL: https://doi.org/10.1182/bloodadvances.2022008788, doi:10.1182/bloodadvances.2022008788. This article has 15 citations and is from a peer-reviewed journal.

  5. (zhang2023separaterolesof pages 8-9): Yuanbao Zhang, Zhigang Liu, and Bin Zhang. Separate roles of lman1 and mcfd2 in er-to-golgi trafficking of fv and fviii. Mar 2023. URL: https://doi.org/10.1182/bloodadvances.2022008788, doi:10.1182/bloodadvances.2022008788. This article has 15 citations and is from a peer-reviewed journal.

  6. (watanabe2024structureoffulllength media 7e4fa169): Satoshi Watanabe, Yoshiaki Kise, Kento Yonezawa, Mariko Inoue, Nobutaka Shimizu, Osamu Nureki, and Kenji Inaba. Structure of full-length ergic-53 in complex with mcfd2 for cargo transport. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46747-1, doi:10.1038/s41467-024-46747-1. This article has 14 citations and is from a highest quality peer-reviewed journal.

  7. (tang2023cargoselectionin pages 9-10): Vi T. Tang and David Ginsburg. Cargo selection in endoplasmic reticulum–to–golgi transport and relevant diseases. The Journal of Clinical Investigation, Jan 2023. URL: https://doi.org/10.1172/jci163838, doi:10.1172/jci163838. This article has 60 citations.

  8. (everett2024lman1servesas pages 6-7): Lesley A. Everett, Zesen Lin, Ann Friedman, Vi T. Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, and Rami Khoriaty. Lman1 serves as a cargo receptor for thrombopoietin. JCI Insight, Dec 2024. URL: https://doi.org/10.1172/jci.insight.175704, doi:10.1172/jci.insight.175704. This article has 1 citations and is from a domain leading peer-reviewed journal.

  9. (everett2024lman1servesas pages 1-2): Lesley A. Everett, Zesen Lin, Ann Friedman, Vi T. Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, and Rami Khoriaty. Lman1 serves as a cargo receptor for thrombopoietin. JCI Insight, Dec 2024. URL: https://doi.org/10.1172/jci.insight.175704, doi:10.1172/jci.insight.175704. This article has 1 citations and is from a domain leading peer-reviewed journal.

  10. (everett2024lman1servesas pages 4-6): Lesley A. Everett, Zesen Lin, Ann Friedman, Vi T. Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, and Rami Khoriaty. Lman1 serves as a cargo receptor for thrombopoietin. JCI Insight, Dec 2024. URL: https://doi.org/10.1172/jci.insight.175704, doi:10.1172/jci.insight.175704. This article has 1 citations and is from a domain leading peer-reviewed journal.

  11. (tang2023cargoselectionin pages 7-8): Vi T. Tang and David Ginsburg. Cargo selection in endoplasmic reticulum–to–golgi transport and relevant diseases. The Journal of Clinical Investigation, Jan 2023. URL: https://doi.org/10.1172/jci163838, doi:10.1172/jci163838. This article has 60 citations.

  12. (yakovleva2024hereditarycombineddeficiency pages 1-3): E. V. Yakovleva, N. I. Zozulya, O. S. Pshenichnikova, V. L. Surin V.L, N. V. Sats, E. B. Orel, A. A. Surenkov, and S. Yu. Mamleeva. Hereditary combined deficiency of factors v and viii: observations in the russian population. Russian journal of hematology and transfusiology, 69:344-355, Nov 2024. URL: https://doi.org/10.35754/0234-5730-2024-69-3-344-355, doi:10.35754/0234-5730-2024-69-3-344-355. This article has 1 citations.

  13. (ma2024rnaitargetinglman1mcfd2 pages 3-5): Siqian Ma, Boyan Liu, Hong Du, Fei Yang, Jingjing Han, Xinqi Huang, Minyang Zhang, Shundong Ji, and Miao Jiang. Rnai targeting lman1-mcfd2 complex promotes anticoagulation in mice. Journal of Thrombosis and Thrombolysis, 57:1349-1362, Sep 2024. URL: https://doi.org/10.1007/s11239-024-03034-6, doi:10.1007/s11239-024-03034-6. This article has 1 citations and is from a peer-reviewed journal.

  14. (ma2024rnaitargetinglman1mcfd2 pages 1-3): Siqian Ma, Boyan Liu, Hong Du, Fei Yang, Jingjing Han, Xinqi Huang, Minyang Zhang, Shundong Ji, and Miao Jiang. Rnai targeting lman1-mcfd2 complex promotes anticoagulation in mice. Journal of Thrombosis and Thrombolysis, 57:1349-1362, Sep 2024. URL: https://doi.org/10.1007/s11239-024-03034-6, doi:10.1007/s11239-024-03034-6. This article has 1 citations and is from a peer-reviewed journal.

  15. (ma2024rnaitargetinglman1mcfd2 pages 9-10): Siqian Ma, Boyan Liu, Hong Du, Fei Yang, Jingjing Han, Xinqi Huang, Minyang Zhang, Shundong Ji, and Miao Jiang. Rnai targeting lman1-mcfd2 complex promotes anticoagulation in mice. Journal of Thrombosis and Thrombolysis, 57:1349-1362, Sep 2024. URL: https://doi.org/10.1007/s11239-024-03034-6, doi:10.1007/s11239-024-03034-6. This article has 1 citations and is from a peer-reviewed journal.

  16. (ma2024rnaitargetinglman1mcfd2 pages 10-12): Siqian Ma, Boyan Liu, Hong Du, Fei Yang, Jingjing Han, Xinqi Huang, Minyang Zhang, Shundong Ji, and Miao Jiang. Rnai targeting lman1-mcfd2 complex promotes anticoagulation in mice. Journal of Thrombosis and Thrombolysis, 57:1349-1362, Sep 2024. URL: https://doi.org/10.1007/s11239-024-03034-6, doi:10.1007/s11239-024-03034-6. This article has 1 citations and is from a peer-reviewed journal.

  17. (watanabe2024structureoffulllength pages 11-12): Satoshi Watanabe, Yoshiaki Kise, Kento Yonezawa, Mariko Inoue, Nobutaka Shimizu, Osamu Nureki, and Kenji Inaba. Structure of full-length ergic-53 in complex with mcfd2 for cargo transport. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46747-1, doi:10.1038/s41467-024-46747-1. This article has 14 citations and is from a highest quality peer-reviewed journal.

  18. (watanabe2024structureoffulllength pages 12-13): Satoshi Watanabe, Yoshiaki Kise, Kento Yonezawa, Mariko Inoue, Nobutaka Shimizu, Osamu Nureki, and Kenji Inaba. Structure of full-length ergic-53 in complex with mcfd2 for cargo transport. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46747-1, doi:10.1038/s41467-024-46747-1. This article has 14 citations and is from a highest quality peer-reviewed journal.

  19. (zhang2023separaterolesof pages 10-11): Yuanbao Zhang, Zhigang Liu, and Bin Zhang. Separate roles of lman1 and mcfd2 in er-to-golgi trafficking of fv and fviii. Mar 2023. URL: https://doi.org/10.1182/bloodadvances.2022008788, doi:10.1182/bloodadvances.2022008788. This article has 15 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. zhang2023separaterolesof pages 8-9
  2. watanabe2024structureoffulllength pages 1-2
  3. tang2023cargoselectionin pages 5-7
  4. yakovleva2024hereditarycombineddeficiency pages 1-3
  5. watanabe2024structureoffulllength pages 11-12
  6. zhang2023separaterolesof pages 1-2
  7. tang2023cargoselectionin pages 9-10
  8. tang2023cargoselectionin pages 7-8
  9. watanabe2024structureoffulllength pages 12-13
  10. zhang2023separaterolesof pages 10-11
  11. https://doi.org/10.1038/s41467-024-46747-1
  12. https://doi.org/10.1172/jci.insight.175704
  13. https://doi.org/10.1182/bloodadvances.2022008788
  14. https://doi.org/10.1007/s11239-024-03034-6
  15. https://doi.org/10.1172/jci163838
  16. https://doi.org/10.35754/0234-5730-2024-69-3-344-355
  17. https://doi.org/10.1038/s41467-024-46747-1,
  18. https://doi.org/10.1172/jci163838,
  19. https://doi.org/10.1182/bloodadvances.2022008788,
  20. https://doi.org/10.1172/jci.insight.175704,
  21. https://doi.org/10.35754/0234-5730-2024-69-3-344-355,
  22. https://doi.org/10.1007/s11239-024-03034-6,

πŸ“š Additional Documentation

Notes

(LMAN1-notes.md)

LMAN1 (P49257) / Protein ERGIC-53 β€” review notes

Identity and overview

LMAN1 (gene synonyms ERGIC53, F5F8D) encodes Protein ERGIC-53, a 510-aa type I
single-pass transmembrane protein of the early secretory pathway. UniProt names it
"Protein ERGIC-53", "ER-Golgi intermediate compartment 53 kDa protein", "Gp58",
"Intracellular mannose-specific lectin MR60", and "Lectin mannose-binding 1".

It is an L-type (leguminous-type) lectin cargo receptor, NOT a glycosidase/mannosidase.
Its luminal carbohydrate-recognition domain (CRD; L-type lectin-like domain, residues 44-267)
binds high-mannose N-glycans in a Ca2+-dependent manner; carbohydrate ligand-binding residues
include 88, 121, 156, 178, 251-253 and Ca2+-binding residues 152, 154, 156, 181
[file:human/LMAN1/LMAN1-uniprot.txt "ligand="Ca(2+)""].

Core molecular function: mannose-specific lectin

  • ERGIC-53 = MR60, an intracellular mannose-specific lectin
    [file:human/LMAN1/LMAN1-uniprot.txt "is identical to MR60, an intracellular mannose-"].
  • UniProt FUNCTION: "Mannose-specific lectin. May recognize sugar residues of glycoproteins..."
    [file:human/LMAN1/LMAN1-uniprot.txt "Mannose-specific lectin"].
  • The F5F8D1 variant W67S (in the CRD) abolishes both MCFD2 interaction and the
    ability to bind D-mannose [file:human/LMAN1/LMAN1-uniprot.txt "ability to bind D-mannose"];
    the paper shows recombinant WT LMAN1 binds D-mannose but the mutant cannot
    PMID:19787799.
  • ERGIC-53 and VIP36 are L-type lectins functioning as cargo receptors for N-linked glycoproteins;
    ERGIC-53 has broad specificity / lower affinity for high-mannose oligosaccharides
    PMID:24498414.

Core cellular component: ERGIC / ER / COPII vesicle

  • Cycles between ER, ERGIC and cis-Golgi. UniProt SUBCELLULAR LOCATION:
    ERGIC membrane (single-pass type I), Golgi apparatus membrane, ER membrane
    [file:human/LMAN1/LMAN1-uniprot.txt "Endoplasmic reticulum-Golgi intermediate"].
  • LMAN1 is "a mannose-binding type 1 transmembrane protein localized to the endoplasmic
    reticulum-Golgi intermediate compartment (ERGIC)" PMID:12717434.
  • ERGIC proteomics enriched ERGIC-53 in ERGIC membranes PMID:15308636.

Core biological process: ER-to-Golgi cargo receptor transport of FV/FVIII

  • LMAN1 + MCFD2 form a cargo receptor that transports coagulation factors V and VIII
    from the ER to the Golgi. MCFD2 is localized to the ERGIC by a Ca2+-dependent interaction
    with LMAN1 PMID:12717434.
  • cargo receptor complex (GO:0062137) β€” LMAN1-MCFD2 (ComplexPortal CPX-8001).
  • Both proteins required, but they have separable roles: cargo binding/transport is
    carried out by MCFD2, with LMAN1 acting primarily as a shuttling carrier of MCFD2;
    N-glycan binding by LMAN1 is not essential for FV/FVIII transport
    PMID:36490287.
  • Structural basis: crystal structures of LMAN1-CRD/MCFD2 complex with Ca2+
    PMID:20138881; ERGIC-53-CRD binds MCFD2
    through a surface remote from the sugar-binding site, sugar-binding independent
    PMID:20142513.

Disease: combined factor V and factor VIII deficiency (F5F8D1, MIM 227300)

  • ERGIC-53 mutations cause combined deficiency of coagulation factors V and VIII; the protein
    may function as a chaperone/receptor for ER-to-Golgi transport of a subset of secreted
    proteins including FV and FVIII PMID:9546392.
  • F5F8D is due to mutations in either LMAN1 or MCFD2 PMID:16304051.
  • MCFD2 C-terminal deletion impairs ERGIC-53 binding and causes F5F8D
    PMID:17971482.
    NOTE: protein folding and blood coagulation are downstream/physiological consequences of
    the cargo-transport role; ERGIC-53 is not itself a folding enzyme. Keep as non-core.

Golgi/ERGIC architecture

  • Cargo receptors Surf4, ERGIC-53, and p25 are required to maintain the architecture of
    ERGIC and Golgi by controlling COPI recruitment; silencing Surf4+ERGIC-53 reduces ERGIC
    clusters and fragments the Golgi without affecting anterograde transport
    PMID:18287528.
  • Golgi organization (GO:0007030, IMP) is supported here. The same paper underpins the
    negated GO:0034498 (early endosome to Golgi transport): ERGIC-53 acts in the ER/ERGIC/Golgi
    early secretory pathway and retrograde COPI recycling, NOT in endosome-to-Golgi traffic,
    consistent with the GOA NOT|involved_in qualifier.

Interactors (bare GO:0005515 protein binding β€” keep as non-core)

From UniProt INTERACTION block and references:
- MCFD2 (Q8NI22) β€” co-receptor; many IPI papers (16304051, 17971482, 19787799, 20138881,
20142513, 33961781, 35271311) record the LMAN1-MCFD2 interaction
[file:human/LMAN1/LMAN1-uniprot.txt "MCFD2; NbExp=15"].
- ERP44 (Q9BS26) β€” thiol-mediated retention; binds the hexameric lectin
PMID:17805346.
- SURF4 (O15260) β€” cargo receptor PMID:18287528.
- RAB3GAP1/RAB3GAP2 (Q15042/Q9H2M9) and UBXN6 (Q9BZV1) β€” via C-terminal tail (UBXD1/p97)
PMID:22337587.
- SERPINA1/alpha-1 antitrypsin (P01009) PMID:31142615.
- BET1 (O15155) β€” ER-to-Golgi SNARE PMID:34779586.
- TMEM115 (Q12893) β€” Golgi retrograde PMID:24806965.
- O75612 (PMID:9774442) β€” oncofetal bile salt-dependent lipase cloning paper; IntAct capture.

Peripheral / over-annotation calls

  • metal ion binding (GO:0046872, EXP DisProt PMID:24498414): Ca2+ is a structural cofactor
    of the CRD; keep as non-core.
  • extracellular matrix (GO:0031012 HDA), extracellular exosome (GO:0070062 HDA),
    membrane (GO:0016020 HDA/TAS), sarcomere (GO:0030017 IEA), endomembrane system
    (GO:0012505 IEA): proteomics/electronic over-annotations; mark over-annotated or non-core.
  • negative regulation of protein localization to mitochondrion (GO:1903748, HMP PMID:24270810):
    high-content parkin RNAi screen hit; peripheral, keep as non-core.

Reactome localization (TAS)

Reactome curates ERGIC-53 in COPII vesicle budding/transport (ER membrane, ERGIC membrane,
ER-to-Golgi transport vesicle membrane). Correct compartments; redundant. Reactome
R-HSA-5694431 "Hexameric LMAN1:MCFD2 bind glycosylated Factor V and VIII precursors" and
R-HSA-947991 "Transport of glycoproteins with Man8 (or Man9) N-glycans to the Golgi" directly
reflect the cargo-receptor function.

Falcon deep-research findings (incorporated 2026-06)

  • NEW structure (2024): full-length cryo-EM of human ERGIC-53/LMAN1 in complex with MCFD2 resolves a
    homotetramer ("four-leaf clover" head + long four-helix-bundle coiled-coil stalk + TM anchor),
    revising the older hexamer model that the current top-level description and Reactome
    R-HSA-5694431 still reference [PMID:38493152 (Watanabe et al., Nat Commun 2024) "Structure of
    full-length ERGIC-53 in complex with MCFD2 for cargo transport"; DOI 10.1038/s41467-024-46747-1].
    The structure proposes cargo capture/release regulation via stalk bending and metal binding,
    including an N-terminal Zn2+ site in MCFD2. Added as a HIGH-relevance reference; description not
    edited (additive-only scope), but this is the strongest current evidence on oligomeric state.
  • NEW cargo (2024): thrombopoietin (TPO) is an LMAN1-dependent, MCFD2-independent cargo.
    Lman1-/- and hepatocyte-specific Lman1-knockout mice have reduced plasma TPO and thrombocytopenia
    despite unchanged hepatic Tpo mRNA; TPO co-IPs with LMAN1 but MCFD2 does not co-IP with TPO
    [PMID:39499573 (Everett et al., JCI Insight 2024) "LMAN1 serves as a cargo receptor for
    thrombopoietin"; DOI 10.1172/jci.insight.175704]. This expands the cargo repertoire beyond
    FV/FVIII/A1AT and links LMAN1 to platelet homeostasis; supports the broader "what cargoes depend on
    LMAN1 vs MCFD2" question already in suggested_questions. Added as HIGH-relevance reference.
  • Cargo-recognition/trafficking-motif synthesis (2023 review): Tang & Ginsburg frame ERGIC-53/LMAN1
    as a prototypical L-type lectin cargo receptor and dissect the cytosolic KKFF motif: FF is
    an ER-exit/COPII determinant and KK mediates COPI-dependent retrieval/recycling [PMID:36594468
    (Tang & Ginsburg, J Clin Invest 2023) "Cargo selection in endoplasmic reticulum-to-Golgi transport
    and relevant diseases"; DOI 10.1172/jci163838]. Consistent with the existing description (dilysine/
    diphenylalanine motif); added as MEDIUM-relevance reference. F5F8D attributed ~70% LMAN1 / ~30%
    MCFD2 (consistent with existing review).
  • Lectin-independent cargo recognition for some clients reaffirmed by Falcon (carbohydrate-binding
    mutants still rescue much FVIII secretion), consistent with PMID:36490287 already in the review
    (MCFD2 carries cargo binding; LMAN1 shuttles). No annotation change.
  • Diagnostic/therapeutic context (Falcon; not gene-function): F5F8D prevalence ~1:1,000,000;
    GalNAc-siRNA knockdown of LMAN1/MCFD2 explored as an anticoagulation strategy in mice (Ma 2024).
    Clinical-implementation only; notes-only, not added to YAML.

Pn Notes

(LMAN1-pn-notes.md)

LMAN1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P49257
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-11
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 39; KEEP_AS_NON_CORE: 19; MARK_AS_OVER_ANNOTATED: 8

PN Consistency Summary

  • Consistency: Deep research ↔ review ↔ PN annotation are internally consistent on identity: LMAN1 is correctly an L-type lectin cargo receptor (D-mannose binding GO:0005537), NOT a glycosidase/mannosidase β€” exactly matching the PN "Lectin chaperone" type. Review core = D-mannose binding + ERβ†’Golgi transport (GO:0006888) of FV/FVIII via the LMAN1-MCFD2 cargo-receptor complex (GO:0062137). No contradictions.
  • PN story / NEW pressure: No NEW GO pressure. The lectin/cargo-receptor functions are fully captured in existing GOA. Falcon additions (cryo-EM tetramer PMID:38493152, TPO cargo PMID:39499573, KKFF motif PMID:36594468) refine but do not require new terms. Conclude: already captured.
  • Evidence alignment: PN dossier is mapping-only (no titles). Review evidence is extensive and PubMed-verified (PMID:12717434, 16304051, 36490287, 24498414, etc.). No shared-citation conflict; the divergence is conceptual (group GO term vs. lectin function), not bibliographic.
  • Verdict: Review strong and PN-consistent on identity (lectin, not mannosidase). PN node correct to leave "Lectin chaperone" unmapped; the inherited groupβ†’GO:0006487 projection is an over-reach for a glycan-reader.

Full Consistency Review

  • UniProt: P49257 (Protein ERGIC-53 / MR60) Β· batch: proteostasis-batch-2026-06-11 Β· review status: COMPLETE, very thorough (~80 annotations; detailed notes + Falcon).
  • PN placement: ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone ; PN-node mapping: type "Lectin chaperone" no_mapping; group "N-glycosylation system" mappedβ†’GO:0006487 (protein N-linked glycosylation, ok_for_propagation, new_to_goa); class/branch no_mapping.
  • Consistency: Deep research ↔ review ↔ PN annotation are internally consistent on identity: LMAN1 is correctly an L-type lectin cargo receptor (D-mannose binding GO:0005537), NOT a glycosidase/mannosidase β€” exactly matching the PN "Lectin chaperone" type. Review core = D-mannose binding + ERβ†’Golgi transport (GO:0006888) of FV/FVIII via the LMAN1-MCFD2 cargo-receptor complex (GO:0062137). No contradictions.
  • PN story / NEW pressure: No NEW GO pressure. The lectin/cargo-receptor functions are fully captured in existing GOA. Falcon additions (cryo-EM tetramer PMID:38493152, TPO cargo PMID:39499573, KKFF motif PMID:36594468) refine but do not require new terms. Conclude: already captured.
  • Mapping strategy: The group projection GO:0006487 (protein N-linked glycosylation) over-reaches for LMAN1. LMAN1 reads high-mannose N-glycans as a cargo receptor; it neither installs (GO:0006487 = attachment via Asn N4) nor processes/trims them. Marked new_to_goa β€” i.e. it would be a brand-new, unsupported assertion. The "N-glycosylation system" group conflates installers (OST), processors (MAN1B1/EDEM) and readers (lectins) under one biosynthesis term that only describes installation. Like the TOMM20/HSPA8/RAB7A precedents, this projected term is broader/wrong-branch relative to the review's actual function and should not propagate to LMAN1.
  • Evidence alignment: PN dossier is mapping-only (no titles). Review evidence is extensive and PubMed-verified (PMID:12717434, 16304051, 36490287, 24498414, etc.). No shared-citation conflict; the divergence is conceptual (group GO term vs. lectin function), not bibliographic.
  • Verdict: Review strong and PN-consistent on identity (lectin, not mannosidase). PN node correct to leave "Lectin chaperone" unmapped; the inherited groupβ†’GO:0006487 projection is an over-reach for a glycan-reader.
    Recommended edits: [MAP] Do not propagate GO:0006487 (protein N-linked glycosylation) to LMAN1 from the "N-glycosylation system" group β€” LMAN1 binds/transports high-mannose glycoproteins, it does not perform N-linked glycosylation; flag the group node as over-broad (mixes installers/processors/readers).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-11
  • review_yaml: genes/human/LMAN1/LMAN1-ai-review.yaml
  • PN workbook rows: 1

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

  • UniProt: P49257
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [type] ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [group] ER proteostasis|Glycoproteostasis|N-glycosylation system
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006487 protein N-linked glycosylation]
      rationale: This PN group captures the ER N-glycosylation machinery that installs and processes N-linked glycans during proteostasis. GO protein N-linked glycosylation is the best current propagation target in the local cache.
    • [class] ER proteostasis|Glycoproteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0006487 protein N-linked glycosylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
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: Ξ±1-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.