LMAN1 (P49257) / Protein ERGIC-53 — 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) — 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 — keep as non-core)

From UniProt INTERACTION block and references:
- MCFD2 (Q8NI22) — 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) — thiol-mediated retention; binds the hexameric lectin
PMID:17805346.
- SURF4 (O15260) — cargo receptor PMID:18287528.
- RAB3GAP1/RAB3GAP2 (Q15042/Q9H2M9) and UBXN6 (Q9BZV1) — via C-terminal tail (UBXD1/p97)
PMID:22337587.
- SERPINA1/alpha-1 antitrypsin (P01009) PMID:31142615.
- BET1 (O15155) — ER-to-Golgi SNARE PMID:34779586.
- TMEM115 (Q12893) — Golgi retrograde PMID:24806965.
- O75612 (PMID:9774442) — 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.