{"gene":"LMAN1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1993,"finding":"ERGIC-53 is a type I membrane protein of the ER-Golgi intermediate compartment whose short cytoplasmic tail contains a dilysine (KKXX) motif that functions as an ER retention/retrieval signal, as demonstrated by cDNA cloning and expression in Vero cells.","method":"cDNA cloning, sequence analysis, heterologous expression with immunofluorescence localization","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — sequence-based identification of dilysine motif confirmed by expression studies, replicated extensively across subsequent papers","pmids":["8223692"],"is_preprint":false},{"year":1994,"finding":"The COOH-terminal dilysine motif of ERGIC-53 mediates both pre-Golgi retention and, when ERGIC-53 reaches the cell surface upon overexpression, lysine-dependent endocytosis; replacing the two critical lysines with serines disrupts both retention and endocytosis.","method":"Site-directed mutagenesis, overexpression in COS cells, cell-surface assay, endocytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional readout in two assays (retention and endocytosis), single lab but orthogonal methods","pmids":["8119975"],"is_preprint":false},{"year":1995,"finding":"The cytoplasmic domain of ERGIC-53 is required and sufficient for pre-medial-Golgi localization, containing a COOH-terminal dilysine ER-retrieval signal (KKFF) and an adjacent RSQQE targeting determinant; the two C-terminal phenylalanines modulate both signals and are required for full recycling through the ER-ERGIC-cis-Golgi pathway.","method":"Domain-swap experiments with CD4 reporter, N-glycosylation/endoglycosidase H resistance assay, immunofluorescence microscopy, site-directed mutagenesis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution via domain swaps plus mutagenesis with multiple readouts, foundational targeting paper","pmids":["7559786"],"is_preprint":false},{"year":1995,"finding":"ERGIC-53 is identical to the intracellular mannose-specific lectin MR60 isolated from myelomonocytic cells; sequence homology to leguminous lectins and galectins was established.","method":"cDNA cloning, peptide sequence matching, sequence homology analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — molecular identity established by cDNA/peptide matching, replicated but no functional assay in this paper","pmids":["7876089"],"is_preprint":false},{"year":1996,"finding":"ERGIC-53 is a functional mannose-selective, calcium-dependent lectin. Overexpressed ERGIC-53 binds mannose columns in a calcium-dependent manner; substitution of a conserved asparagine in the putative carbohydrate recognition domain (CRD), or a second CRD-site residue, abolishes mannose binding and co-staining with mannosylated neoglycoprotein.","method":"Mannose-affinity chromatography of overexpressed protein, morphological binding assay with mannosylated neoglycoprotein, site-directed mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay plus mutagenesis, replicated in subsequent structural and biochemical work","pmids":["8868475"],"is_preprint":false},{"year":1997,"finding":"ERGIC-53 carries a C-terminal cytoplasmic phenylalanine-dependent ER-exit determinant that interacts directly with the COPII coat component Sec23p; the two terminal phenylalanines are essential for ER exit and for this interaction.","method":"Site-directed mutagenesis, in vitro peptide binding assay with Sec23p, subcellular trafficking assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of COPII interaction plus mutagenesis, defining mechanism replicated across labs","pmids":["9395526"],"is_preprint":false},{"year":1998,"finding":"ERGIC-53 cycles continuously through ER, ERGIC, and cis-Golgi; the major retrograde recycling pathway of ERGIC-53 bypasses the Golgi apparatus, returning directly from ERGIC to ER, as shown by temperature-shift experiments and immunogold electron microscopy.","method":"Temperature-shift experiments, immunofluorescence microscopy, immunogold electron microscopy, density-gradient centrifugation in HepG2 cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal imaging and biochemical methods, replicated in multiple cell types","pmids":["9788882"],"is_preprint":false},{"year":1998,"finding":"Mistargeting ERGIC-53 to the ER (by a retention mutant that sequesters endogenous ERGIC-53) specifically impairs secretion of cathepsin C precursor while leaving other lysosomal enzymes and membrane glycoproteins unaffected, establishing that ERGIC-53 recycling is required for efficient transport of a selective subset of glycoproteins.","method":"Tetracycline-inducible expression of ER-retention mutant in HeLa cells, metabolic labeling, immunoprecipitation of secreted glycoproteins","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific substrate-level readout, foundational cargo-receptor paper","pmids":["9679138"],"is_preprint":false},{"year":1998,"finding":"Mutations in ERGIC-53 (null mutations) cause combined deficiency of coagulation factors V and VIII, identifying ERGIC-53 as an ER-to-Golgi molecular chaperone/transport receptor required for secretion of FV and FVIII.","method":"Positional cloning, DNA sequence analysis, immunofluorescence and Western blot of patient lymphocytes","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease gene identification by positional cloning confirmed by protein absence in patient cells, replicated widely","pmids":["9546392"],"is_preprint":false},{"year":1999,"finding":"ERGIC-53 functions as a cargo transport receptor for glycoproteins: it binds a cathepsin-Z-related glycoprotein in the ER in a carbohydrate- and calcium-dependent manner, and cargo dissociation occurs in the ERGIC. Binding does not require ERGIC-53 oligomerization, but oligomerization is required for ER exit of ERGIC-53 itself.","method":"Co-immunoprecipitation, calcium-depletion and glycan-modification experiments, temperature-block assays, mislocalization studies","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with mechanistic dissection of Ca2+/carbohydrate dependence, multiple orthogonal conditions, widely replicated","pmids":["10559958"],"is_preprint":false},{"year":1999,"finding":"The sugar-binding ability of ERGIC-53 (MR60) requires a dimeric state: a truncated protein retaining Cys466 (but not Cys475) forms dimers and binds mannosides, whereas a shorter construct lacking both cysteines neither dimerizes nor binds mannose.","method":"Expression of recombinant truncated proteins, mannose-column binding, immunoprecipitation/SDS-PAGE oligomerization analysis","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and oligomerization assay, single lab, two orthogonal methods","pmids":["10521535"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the carbohydrate recognition domain (CRD) of rat p58/ERGIC-53 determined to 1.46 Å resolution (calcium-free form); the fold resembles leguminous lectins with a beta-sandwich and a negatively charged ligand-binding cleft; a conserved surface patch on the opposite face is implicated in protein-protein interactions and oligomerization.","method":"X-ray crystallography at 1.46 Å resolution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional interpretation, independently extended by subsequent structural studies","pmids":["11850423"],"is_preprint":false},{"year":2003,"finding":"ER export of ERGIC-53 requires three cooperating determinants: (1) a C-terminal phenylalanine motif for COPII interaction, assisted by a cytoplasmic glutamine; (2) disulfide-bond-stabilized hexamerization dependent on polar and aromatic residues in the transmembrane domain; (3) optimal transmembrane domain length of 21 amino acids. Together these reconstitute full transport activity.","method":"Site-directed mutagenesis, endoglycosidase H resistance assay, immunofluorescence, reconstitution with signal-less construct","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis combined with reconstitution in a single rigorous study","pmids":["13130098"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the CRD of p58/ERGIC-53 in the calcium-bound form reveals two calcium-binding sites 6 Å apart (one novel, one homologous to plant lectins), large conformational changes in the ligand-binding site upon calcium binding, and absence of the short loop present in plant lectins, consistent with preference for Man8GlcNAc2 glycans at ER exit.","method":"X-ray crystallography (calcium-bound form)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure independently confirming and extending the 2002 structure","pmids":["14643651"],"is_preprint":false},{"year":2003,"finding":"LMAN1 interacts with coagulation factor VIII in vivo via co-immunoprecipitation; the interaction is mediated by both high-mannose N-linked oligosaccharides in the B domain of FVIII and protein-protein contacts.","method":"Co-immunoprecipitation from transfected HeLa and COS-1 cells, glycosylation modification experiments","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with mechanistic follow-up (glycan vs. protein contribution), single lab","pmids":["14629470"],"is_preprint":false},{"year":2004,"finding":"pH-induced conversion of ERGIC-53 triggers glycoprotein cargo release: ERGIC-53 binds mannose efficiently at pH 7.4 (ER pH) but not at slightly lower pH (ERGIC pH); a conserved histidine in the CRD center is required for lectin activity and acts as a molecular pH/Ca2+ sensor. Organelle neutralization impairs cargo dissociation in the ERGIC.","method":"In vitro mannose-binding assay at varying pH and Ca2+ concentrations, histidine mutagenesis, acidification of live cells, organelle pH neutralization, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis plus cell-based validation, orthogonal methods in one study","pmids":["14718532"],"is_preprint":false},{"year":2005,"finding":"LMAN1 and MCFD2 form a stoichiometric 1:1 complex in cells; MCFD2 is retained in the ER via its interaction with LMAN1. Both LMAN1 and MCFD2 interact specifically with factor VIII (primarily via the B domain) in a calcium-dependent, glycosylation-independent manner. MCFD2 can interact with FVIII independently of LMAN1-MCFD2 complex formation.","method":"Co-immunoprecipitation, cross-linking-immunoprecipitation, stoichiometry analysis, Western blot, calcium chelation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with cross-linking, stoichiometry determination, mechanistic dissection with multiple conditions, replicated","pmids":["15886209"],"is_preprint":false},{"year":2005,"finding":"ERGIC-53 forms exclusively hexameric complexes in cells, existing in two forms: covalent disulfide-linked and non-covalent SDS-sensitive hexamers assembled from three disulfide-linked dimers via coiled-coil interactions. Neither membrane-proximal cysteine is essential for hexamer formation or intracellular ERGIC distribution.","method":"Sucrose gradient sedimentation, chemical cross-linking, non-denaturing gel electrophoresis, subcellular fractionation, cysteine mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods, mutagenesis, single rigorous study","pmids":["16257008"],"is_preprint":false},{"year":2006,"finding":"MCFD2 is required for the ERGIC-53-dependent ER export of coagulation factors V and VIII but is dispensable for ERGIC-53 binding to cathepsin Z and cathepsin C; in the absence of ERGIC-53, MCFD2 is secreted rather than retained in the ER, establishing ERGIC-53 as the membrane anchor of the complex.","method":"siRNA knockdown of ERGIC-53 and MCFD2, YFP fragment complementation assay in vivo, localization studies","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with specific cargo readouts plus protein-fragment complementation, cargo selectivity defined","pmids":["17010120"],"is_preprint":false},{"year":2007,"finding":"Frontal affinity chromatography shows ERGIC-53 binds high-mannose oligosaccharides with low affinity and broad specificity, not distinguishing between monoglucosylated and deglucosylated high-mannose N-glycans; single amino acid substitutions in the CRD can switch the sugar-binding properties.","method":"Frontal affinity chromatography with pyridylaminated sugar library, structure-based mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro binding assay with mutagenesis, single lab but rigorous","pmids":["18025080"],"is_preprint":false},{"year":2007,"finding":"MCFD2 binding to ERGIC-53 is enhanced when MCFD2 is present; ERGIC-53 sugar binding is enhanced by its interaction with MCFD2 as shown by flow cytometry and surface plasmon resonance; F5F8D patient MCFD2 missense mutations drastically reduce binding affinity to ERGIC-53; the interaction is Ca2+-dependent (weakened below 0.2 mM Ca2+).","method":"Flow cytometry with biotinylated soluble ERGIC-53, surface plasmon resonance, endo-H treatment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative binding assays (SPR + flow cytometry), two orthogonal methods, Ca2+ dependence quantified","pmids":["18056485"],"is_preprint":false},{"year":2008,"finding":"ERGIC-53 is an intracellular transport receptor for alpha1-antitrypsin (α1-AT): ERGIC-53 binds α1-AT in a carbohydrate- and conformation-dependent manner; ERGIC-53 knockdown and knockout cells show a specific secretion defect of α1-AT that is corrected by ERGIC-53 re-expression.","method":"YFP-based protein fragment complementation screening of cDNA library, siRNA knockdown, ERGIC-53 KO cell reconstitution, secretion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including KO rescue, carbohydrate/conformation dependence established","pmids":["18283111"],"is_preprint":false},{"year":2008,"finding":"SUMF1 interacts with ERGIC-53 in the early secretory pathway; ERGIC-53 favors SUMF1 export from the ER; silencing ERGIC-53 causes proteasomal degradation of SUMF1.","method":"Co-immunoprecipitation, siRNA silencing with SUMF1 trafficking and stability assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional silencing experiment, single lab, two methods","pmids":["18508857"],"is_preprint":false},{"year":2008,"finding":"Surf4 interacts with ERGIC-53; co-silencing of Surf4 and ERGIC-53 (but not either alone) reduces the number of ERGIC clusters and fragments the Golgi, partially redistributing COPI but not Golgi matrix proteins, establishing that cargo receptors collectively maintain ERGIC and Golgi architecture by controlling COPI recruitment.","method":"siRNA knockdown (single and double), co-immunoprecipitation, live imaging of ERGIC stability, immunofluorescence for COPI and Golgi markers, BFA resistance assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockdown plus co-IP and live imaging, multiple orthogonal readouts","pmids":["18287528"],"is_preprint":false},{"year":2009,"finding":"The C-terminal EF-hand domains of MCFD2 are both necessary and sufficient for interaction with LMAN1; these same EF-hand domains also mediate interaction with FV and FVIII but via a site separable from the LMAN1-binding site; Ca2+-induced folding is important for LMAN1 interaction but not for FV/FVIII binding.","method":"MCFD2 deletion and missense mutant analysis, co-immunoprecipitation, circular dichroism spectroscopy","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus CD spectroscopy plus co-IP, orthogonal methods defining separate binding sites","pmids":["20007547"],"is_preprint":false},{"year":2010,"finding":"The LMAN1 CRD contains distinct, separable binding sites for MCFD2 (N-terminal beta sheet) and for FV/FVIII cargo (Ca2+- and sugar-binding sites); monomeric LMAN1 mutants are defective in ER exit and cannot interact with MCFD2, indicating oligomerization is necessary for cargo receptor function.","method":"Mutagenesis of LMAN1 CRD, co-immunoprecipitation, FVIII interaction assays, oligomerization analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis separating binding sites with multiple functional readouts, consistent with crystal structures","pmids":["20817851"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the LMAN1-CRD/MCFD2 complex reveals the protein-protein interaction interface; circular dichroism shows that most F5F8D missense mutations in MCFD2 cause global destabilization, while stable mutations map to the LMAN1-binding surface.","method":"X-ray crystallography of LMAN1-CRD/MCFD2 complex, circular dichroism of MCFD2 mutants","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biophysical characterization of disease mutants","pmids":["20138881"],"is_preprint":false},{"year":2011,"finding":"LMAN1-deficient mice exhibit ~50% reductions in plasma FV and FVIII and platelet FV; ER in hepatocytes is slightly distended with accumulation of α1-antitrypsin and GRP78; no significant effect on cathepsin C or Z levels in liver or α1-antitrypsin in plasma under normal conditions.","method":"Lman1 knockout mouse analysis, plasma coagulation factor assays, liver histology and EM, protein level analysis by Western blot","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with multiple substrate-specific readouts","pmids":["21795745"],"is_preprint":false},{"year":2012,"finding":"UBXD1 interacts with ERGIC-53 via the N-terminal 10 residues of UBXD1 and the C-terminal cytoplasmic tail of ERGIC-53; this interaction requires p97 ATPase activity but not ubiquitin modification; UBXD1 modulates subcellular trafficking of ERGIC-53 including promoting its movement to the cell membrane.","method":"LC-MS/MS interactome, co-immunoprecipitation, SILAC proteomic profiling, localization studies, p97/E1 inhibitor experiments","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP confirmed by MS, localization study, p97 inhibitor experiment, single lab","pmids":["22337587"],"is_preprint":false},{"year":2012,"finding":"Under ER stress, ERGIC-53 redistributes from broad ER/Golgi distribution to compact Golgi localization; this redistribution is abrogated by co-expression of VIPL; ERGIC-53 co-precipitates with VIPL but not VIP36, indicating VIPL interaction regulates ERGIC-53 localization.","method":"Monoclonal antibody generation, immunostaining, flow cytometry, co-immunoprecipitation, UPR induction with tunicamycin","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus localization under defined stress conditions, single lab","pmids":["22821029"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of ERGIC-53-CRD complexed with MCFD2 and α1,2-mannotriose reveals that ERGIC-53 can bind the D1 trimannosyl arm in two alternative modes; a single Asp-to-Gly substitution creates a shallower sugar-binding pocket compared to VIP36, enabling ERGIC-53 to accommodate terminal glucose residues.","method":"X-ray crystallography of ternary complex (ERGIC-53-CRD/MCFD2/mannotriose)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution ternary crystal structure defining molecular basis of broad sugar specificity","pmids":["24498414"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of LMAN1-CRD bound to Man-α-1,2-Man define the central mannose-binding site; mutagenesis identifies His178 and Gly251/252 as critical for FV/FVIII binding; mannobiose binding is relatively pH-independent but sensitive to lowered Ca2+ concentrations, suggesting Ca2+ regulates cargo release.","method":"X-ray crystallography, site-directed mutagenesis, in vitro binding assays, pH and Ca2+ titration","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and quantitative binding assays in one study","pmids":["23709226"],"is_preprint":false},{"year":2013,"finding":"ERGIC-53 is required for production of infectious arenavirus, coronavirus, and filovirus particles; ERGIC-53 associates with viral glycoproteins through a lectin-independent mechanism, traffics to budding sites, and is incorporated into virions; in its absence, GP-containing virus particles form but are non-infectious due to impaired host-cell attachment.","method":"siRNA knockdown, co-immunoprecipitation, live-cell imaging, viral infectivity and particle formation assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with specific infectivity readout plus co-IP and imaging, multiple virus families tested","pmids":["24237698"],"is_preprint":false},{"year":2013,"finding":"Mac-2BP (Mac-2 binding protein) is a novel ERGIC-53 cargo glycoprotein; interaction requires high-mannose-type N-glycan binding by ERGIC-53; ERGIC-53 ER-mistargeting mutant blocks Mac-2BP transport; MCFD2 is also involved in Mac-2BP secretion.","method":"GFP fragment complementation cDNA library screen, N-glycan-binding-deficient mutant (N156A), ER-mistargeting mutant (KKAA), glycosylation inhibitors, co-immunoprecipitation","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation screen plus mutant and inhibitor validation, single lab","pmids":["23550150"],"is_preprint":false},{"year":2015,"finding":"LMAN1 interacts with N-glycosylated MMP-9 in the ER and is required for efficient MMP-9 secretion; N-glycosylation-deficient MMP-9 is secretion-compromised; LMAN1 knockout cells show reduced MMP-9 secretion.","method":"Protein fragment complementation assay, co-immunoprecipitation, LMAN1 KO cell secretion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — complementation assay plus co-IP plus KO functional assay, single lab, two orthogonal approaches","pmids":["26150355"],"is_preprint":false},{"year":2018,"finding":"MCFD2-deficient mice have lower plasma FV and FVIII than LMAN1-deficient mice; doubly deficient mice match LMAN1-deficient levels, suggesting an alternative FVIII secretion pathway exists. Both LMAN1 and MCFD2 deficiency cause decreased plasma α1-antitrypsin in male mice and comparable ER accumulation of AAT in hepatocytes.","method":"Mouse gene targeting (MCFD2 KO), plasma coagulation factor assays, comparison of singly and doubly deficient mice, hepatocyte ER analysis","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double KO genetic epistasis with multiple quantitative cargo readouts","pmids":["29735583"],"is_preprint":false},{"year":2019,"finding":"LMAN1 promotes surface trafficking of GABAAR β3 subunits in mouse hypothalamic neurons; LMAN1 KO mice show decreased total protein levels of 5HT3A receptors and GABAAR γ2 subunits; LMAN1 interacts with GABAARs in a glycan-independent manner; LMAN1 KO upregulates ERp44 without changing calnexin.","method":"siRNA knockdown, Western blot of brain homogenates from LMAN1 KO mice, surface trafficking assay, co-immunoprecipitation with glycan-independence test","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus co-IP with mechanistic follow-up, single lab, novel substrate class","pmids":["30791981"],"is_preprint":false},{"year":2020,"finding":"HBV exploits ERGIC-53 for viral particle propagation; ERGIC-53 interacts with the N146-glycan of the HBV envelope in a productive, lectin-dependent manner; ERGIC-53 silencing blocks infectious viral particle exit but not subviral particle exit; ERGIC-53 acts after nucleocapsid envelopment in conjunction with ESCRT components.","method":"siRNA silencing, molecular interaction studies, cell imaging in HBV-expressing liver cells, particle infectivity assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — silencing with specific viral vs. subviral particle readout, interaction mapped to specific glycan, single lab","pmids":["32806600"],"is_preprint":false},{"year":2020,"finding":"Multiple crystal forms of the ERGIC-53-CRD/MCFD2 complex at up to 1.60 Å resolution reveal that MCFD2 (but not ERGIC-53-CRD) exhibits significant conformational plasticity potentially enabling accommodation of diverse polypeptide cargo ligands.","method":"X-ray crystallography (multiple crystal forms, 1.60 Å best resolution)","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple crystal structures revealing conformational dynamics, single lab","pmids":["32356523"],"is_preprint":false},{"year":2021,"finding":"ERp44 binds ERGIC-53 in the ER to negotiate preferential loading into COPII vesicles; silencing ERGIC-53 causes secretion of Prdx4 (an ERp44-retained client), establishing that ERGIC-53 couples transport of cargo and quality-control inspector proteins.","method":"Co-immunoprecipitation, ERGIC-53 siRNA silencing with Prdx4 secretion readout, 4-phenylbutyrate COPII competition","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus knockdown with specific cargo readout, mechanistic model with pharmacological validation, single lab","pmids":["33763635"],"is_preprint":false},{"year":2022,"finding":"The LMAN1-MCFD2 complex is a cargo receptor for AAT ER-to-Golgi transport: LMAN1 and MCFD2 KO HepG2 and HEK293T cells show reduced AAT secretion and elevated intracellular AAT due to delayed ER-to-Golgi transport; rescue requires wild-type but not mutant proteins; elimination of the second glycosylation site of AAT abolishes LMAN1-dependent secretion; AAT interaction with LMAN1 is independent of MCFD2.","method":"CRISPR KO of LMAN1 and MCFD2, secretion assays, intracellular AAT quantification, rescue with wild-type and mutant proteins, glycosylation site mutagenesis, co-immunoprecipitation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with rescue, mutagenesis of cargo glycosylation site, co-IP, multiple orthogonal methods","pmids":["35322856"],"is_preprint":false},{"year":2023,"finding":"LMAN1 carbohydrate binding is not essential for FV/FVIII transport; overexpression of MCFD2 alone (wild-type or mutant) rescues FV/FVIII secretion in LMAN1-deficient cells, suggesting MCFD2 performs cargo binding/transport and LMAN1 primarily functions as a transmembrane shuttling carrier for MCFD2.","method":"Multiple LMAN1/MCFD2 KO cell lines, FV/FVIII secretion assays, carbohydrate-binding mutant rescue, MCFD2 overexpression rescue","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines with rescue experiments and carbohydrate binding mutants, single lab, challenges existing model","pmids":["36490287"],"is_preprint":false},{"year":2023,"finding":"LMAN1 directly binds house dust mite (HDM) allergens on the surface of dendritic cells and airway epithelial cells; LMAN1 overexpression downregulates NF-κB signaling in response to HDM or inflammatory cytokines; HDM promotes LMAN1 binding to FcRγ and recruitment of SHP1.","method":"Receptor glycocapture screen, direct binding verification, overexpression NF-κB reporter assay, co-immunoprecipitation (LMAN1-FcRγ), SHP1 recruitment assay, in vivo localization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple binding and signaling assays, single lab, novel surface receptor function","pmids":["36870056"],"is_preprint":false},{"year":2024,"finding":"LMAN1 is a cargo receptor for thrombopoietin (TPO): hepatocyte-specific (but not hematopoietic) LMAN1 deletion causes thrombocytopenia with reduced plasma TPO despite normal Tpo mRNA; TPO co-immunoprecipitates with LMAN1; TPO accumulates intracellularly in LMAN1-deleted cells; TPO secretion is MCFD2-independent.","method":"Conditional hepatocyte-specific and hematopoietic-specific Lman1 KO mice, platelet and MK quantification, plasma TPO measurement, co-immunoprecipitation, intracellular TPO accumulation assay","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO mice with specific cargo (TPO) readout, co-IP, intracellular accumulation, MCFD2-independence established","pmids":["39499573"],"is_preprint":false}],"current_model":"LMAN1 (ERGIC-53) is a hexameric type I transmembrane lectin that cycles between the ER, ERGIC, and cis-Golgi via COPII-mediated anterograde transport (driven by a C-terminal FF motif interacting with Sec23/24) and COPI-mediated retrograde retrieval (driven by a dilysine KKXX motif); in the ER lumen it functions as a cargo receptor by binding high-mannose N-glycans on a select subset of secretory glycoproteins—including coagulation factors V and VIII, α1-antitrypsin, cathepsins C and Z, MMP-9, TPO, and neuroreceptors—in a calcium- and pH-dependent manner, releasing cargo in the more acidic ERGIC; for FV/FVIII export it forms a 1:1 complex with the soluble EF-hand protein MCFD2, which provides an additional polypeptide-recognition surface for these coagulation factors, while LMAN1 itself primarily serves as the transmembrane carrier shuttling MCFD2; loss-of-function mutations in LMAN1 cause the bleeding disorder combined deficiency of factors V and VIII (F5F8D)."},"narrative":{"mechanistic_narrative":"LMAN1 (ERGIC-53) is a hexameric type I transmembrane lectin that operates as a glycoprotein cargo receptor in the early secretory pathway, cycling continuously between the ER, ERGIC, and cis-Golgi [PMID:9788882, PMID:16257008]. Its short cytoplasmic tail encodes the dual trafficking logic of this cycle: a C-terminal phenylalanine motif that binds the COPII coat component Sec23 to drive ER exit, and a dilysine (KKXX) motif that mediates retrograde retrieval and, upon surface escape, lysine-dependent endocytosis [PMID:8119975, PMID:9395526]. Full ER export is reconstituted by three cooperating determinants—the COPII phenylalanine signal, disulfide- and coiled-coil-stabilized hexamerization, and an optimal transmembrane domain length [PMID:13130098]. Within the ER lumen, its leguminous-lectin-fold carbohydrate recognition domain binds high-mannose N-glycans with broad, low-affinity specificity in a calcium-dependent manner [PMID:8868475, PMID:11850423, PMID:18025080], and a conserved CRD histidine acts as a pH/Ca2+ sensor so that cargo is captured at ER pH and released in the more acidic ERGIC [PMID:14718532]. Through this mechanism LMAN1 selectively promotes ER-to-Golgi transport of a defined subset of secretory glycoproteins, including cathepsin C and cathepsin Z, alpha1-antitrypsin, Mac-2BP, MMP-9, and thrombopoietin [PMID:9679138, PMID:10559958, PMID:18283111, PMID:23550150, PMID:26150355, PMID:39499573]. For coagulation factors V and VIII, LMAN1 forms a stoichiometric 1:1 complex with the soluble EF-hand protein MCFD2, which it anchors in the ER and which contributes an additional polypeptide-recognition surface; the MCFD2- and cargo/sugar-binding sites on the CRD are structurally separable [PMID:15886209, PMID:20817851, PMID:20138881, PMID:24498414]. Loss-of-function mutations in LMAN1 cause the autosomal recessive bleeding disorder combined deficiency of coagulation factors V and VIII (F5F8D) [PMID:9546392]. Beyond its secretory role, LMAN1 is exploited by multiple enveloped viruses for production of infectious particles [PMID:24237698, PMID:32806600] and functions at the cell surface as a receptor for house dust mite allergens that dampens NF-κB signaling [PMID:36870056].","teleology":[{"year":1994,"claim":"Established that LMAN1's cytoplasmic dilysine motif is the operational signal for pre-Golgi retention, answering how the protein is confined to the early secretory pathway.","evidence":"Site-directed mutagenesis of the KKXX lysines with retention and endocytosis assays in COS cells","pmids":["8119975"],"confidence":"High","gaps":["Did not identify the retrograde coat machinery (COPI) recognizing the motif","Surface endocytosis was an overexpression artifact, not the physiological route"]},{"year":1995,"claim":"Defined the cytoplasmic domain as necessary and sufficient for cis-Golgi recycling localization and identified an adjacent phenylalanine determinant, resolving the bidirectional targeting code.","evidence":"CD4 reporter domain-swap experiments with endoglycosidase H resistance and immunofluorescence readouts","pmids":["7559786"],"confidence":"High","gaps":["Anterograde coat partner of the phenylalanine motif not yet identified","Luminal cargo-binding function not addressed"]},{"year":1996,"claim":"Demonstrated that LMAN1 is a functional mannose-selective, calcium-dependent lectin, providing the molecular basis for glycoprotein cargo recognition.","evidence":"Mannose-affinity chromatography of overexpressed protein plus CRD-residue mutagenesis abolishing binding","pmids":["8868475"],"confidence":"High","gaps":["Physiological cargo glycoproteins not yet identified","Glycan specificity not quantified"]},{"year":1997,"claim":"Showed the C-terminal phenylalanine ER-exit determinant binds COPII Sec23 directly, defining the anterograde transport mechanism.","evidence":"In vitro peptide binding assay with Sec23p plus mutagenesis and trafficking readouts","pmids":["9395526"],"confidence":"High","gaps":["Did not address Sec24 cargo-adaptor contribution","Oligomerization requirement for exit not yet established"]},{"year":1998,"claim":"Connected LMAN1 to human disease by showing null mutations cause combined factor V and VIII deficiency, establishing its physiological role as an FV/FVIII transport receptor.","evidence":"Positional cloning and sequencing in F5F8D patients with protein-absence confirmation in patient cells","pmids":["9546392"],"confidence":"High","gaps":["Mechanism of FV/FVIII recognition not defined","Did not explain why only FV and FVIII are affected"]},{"year":1998,"claim":"Demonstrated cargo selectivity by showing that ER mistargeting of LMAN1 impairs cathepsin C secretion specifically, establishing the cargo-receptor concept for a defined glycoprotein subset.","evidence":"Inducible ER-retention mutant in HeLa cells with metabolic labeling and secretion immunoprecipitation","pmids":["9679138"],"confidence":"High","gaps":["Direct cargo binding not shown in this study","Full cargo repertoire unknown"]},{"year":1999,"claim":"Provided direct mechanistic proof that LMAN1 binds glycoprotein cargo in the ER in a carbohydrate- and calcium-dependent manner and releases it in the ERGIC, separating binding from oligomerization requirements.","evidence":"Co-immunoprecipitation of a cathepsin-Z-related glycoprotein with calcium-depletion, glycan-modification and temperature-block assays","pmids":["10559958"],"confidence":"High","gaps":["Trigger for ERGIC release not yet defined","Stoichiometry of cargo capture unknown"]},{"year":2002,"claim":"Solved the CRD crystal structure, revealing a leguminous-lectin fold with a ligand-binding cleft and an oligomerization patch, framing the structural basis of lectin and protein-protein function.","evidence":"X-ray crystallography of rat CRD at 1.46 Å (calcium-free)","pmids":["11850423"],"confidence":"High","gaps":["Calcium-bound conformation not captured","Glycan-bound complex not resolved"]},{"year":2003,"claim":"Captured the calcium-bound CRD, showing two calcium sites and ligand-site conformational changes consistent with high-mannose glycan preference, explaining calcium-dependent cargo capture.","evidence":"X-ray crystallography of the calcium-bound CRD form","pmids":["14643651"],"confidence":"High","gaps":["Did not resolve how calcium loss drives cargo release in cells","pH contribution not addressed structurally"]},{"year":2003,"claim":"Defined three cooperating ER-export determinants—COPII phenylalanine signal, disulfide/coiled-coil hexamerization, and transmembrane length—reconstituting full transport competence.","evidence":"Systematic mutagenesis with endoglycosidase H resistance and reconstitution of a signal-less construct","pmids":["13130098"],"confidence":"High","gaps":["Did not address luminal cargo loading during assembly","Retrograde KKXX coupling not examined"]},{"year":2004,"claim":"Identified a pH/Ca2+-sensing CRD histidine as the molecular switch that releases cargo in the slightly acidic ERGIC, resolving the directionality of the capture-release cycle.","evidence":"In vitro mannose-binding at varying pH/Ca2+, histidine mutagenesis and live-cell organelle neutralization with co-IP","pmids":["14718532"],"confidence":"High","gaps":["Did not reconcile pH sensitivity differences seen with mannobiose in later work","In vivo pH gradient values inferred indirectly"]},{"year":2005,"claim":"Established the hexameric quaternary architecture (three disulfide-linked dimers via coiled coils), defining the functional oligomeric unit of the receptor.","evidence":"Sucrose gradients, cross-linking, non-denaturing gels and cysteine mutagenesis","pmids":["16257008"],"confidence":"High","gaps":["Functional contribution of covalent vs non-covalent hexamers to cargo transport not fully resolved"]},{"year":2005,"claim":"Discovered the stoichiometric 1:1 LMAN1-MCFD2 complex and showed LMAN1 retains MCFD2 in the ER, revealing a two-component receptor for FVIII binding.","evidence":"Reciprocal co-IP, cross-linking, stoichiometry analysis and calcium-chelation experiments","pmids":["15886209"],"confidence":"High","gaps":["Relative cargo-binding contributions of LMAN1 vs MCFD2 not yet dissected","Binding-site locations on each protein undefined"]},{"year":2006,"claim":"Showed MCFD2 is specifically required for FV/FVIII export but dispensable for cathepsin binding, and that LMAN1 anchors MCFD2, defining cargo-class-specific division of labor.","evidence":"siRNA knockdown of LMAN1 and MCFD2 with YFP fragment complementation and localization in vivo","pmids":["17010120"],"confidence":"High","gaps":["Did not establish whether MCFD2 alone can bind/transport cargo","Mechanism of cargo discrimination unclear"]},{"year":2007,"claim":"Quantified LMAN1 glycan specificity as broad, low-affinity high-mannose binding tunable by single CRD substitutions, refining the lectin recognition model.","evidence":"Frontal affinity chromatography with a pyridylaminated sugar library plus structure-based mutagenesis","pmids":["18025080"],"confidence":"High","gaps":["Did not link specific glycan structures to particular cargo proteins in cells"]},{"year":2007,"claim":"Demonstrated cooperative, calcium-dependent LMAN1-MCFD2 binding and that F5F8D MCFD2 missense mutations weaken the interaction, mechanistically linking complex assembly to disease.","evidence":"Flow cytometry with biotinylated soluble LMAN1 and surface plasmon resonance","pmids":["18056485"],"confidence":"High","gaps":["Did not resolve the atomic interface","Effect on cargo transport rates not measured"]},{"year":2008,"claim":"Identified alpha1-antitrypsin as a conformation- and carbohydrate-dependent LMAN1 cargo via an unbiased complementation screen with KO rescue, broadening the physiological cargo set.","evidence":"YFP fragment complementation cDNA screen, siRNA knockdown and KO cell reconstitution secretion assays","pmids":["18283111"],"confidence":"High","gaps":["MCFD2 involvement in AAT transport not yet tested","Specific AAT glycosite not mapped here"]},{"year":2008,"claim":"Showed that cargo receptors collectively maintain ERGIC and Golgi architecture by controlling COPI recruitment, placing LMAN1 in a redundant transport-receptor network with Surf4.","evidence":"Single and double siRNA knockdown with live imaging, co-IP and COPI/Golgi marker immunofluorescence","pmids":["18287528"],"confidence":"High","gaps":["Direct vs indirect contribution to COPI recruitment unresolved","Whether LMAN1 and Surf4 share cargo not addressed"]},{"year":2009,"claim":"Mapped MCFD2's C-terminal EF-hand domains as both necessary and sufficient for LMAN1 binding, with a separable site for FV/FVIII, refining the architecture of the two-component receptor.","evidence":"MCFD2 deletion/missense mutant co-IP plus circular dichroism spectroscopy","pmids":["20007547"],"confidence":"High","gaps":["Atomic-resolution interface not yet solved here","Calcium dependence of cargo vs LMAN1 binding only partially separated"]},{"year":2010,"claim":"Localized separable MCFD2- and cargo/sugar-binding sites on the LMAN1 CRD and showed oligomerization is required for both ER exit and MCFD2 binding, integrating structure with function.","evidence":"CRD mutagenesis with co-IP, FVIII interaction and oligomerization assays, plus crystal structure of the CRD/MCFD2 complex with CD of disease mutants","pmids":["20817851","20138881"],"confidence":"High","gaps":["Glycan-bound ternary structure not yet captured","Why most F5F8D MCFD2 mutations destabilize rather than block binding still being worked out"]},{"year":2011,"claim":"Established an in vivo LMAN1 KO mouse showing ~50% FV/FVIII reductions and ER accumulation of alpha1-antitrypsin, validating physiological cargo relationships in a whole organism.","evidence":"Lman1 knockout mouse plasma factor assays, liver histology/EM and Western blot","pmids":["21795745"],"confidence":"High","gaps":["Partial (not complete) FV/FVIII loss implied redundancy","Cathepsin levels unaffected, leaving cargo hierarchy unexplained"]},{"year":2013,"claim":"Provided structural and biochemical bases for broad sugar specificity and FV/FVIII recognition, including a ternary glycan complex and identification of critical CRD residues.","evidence":"X-ray crystallography of CRD/MCFD2/mannotriose and CRD/Man-α-1,2-Man complexes with mutagenesis and pH/Ca2+ titration","pmids":["24498414","23709226"],"confidence":"High","gaps":["Discrepant pH dependence between sugar species not fully reconciled","Direct cargo-glycan co-structures absent"]},{"year":2013,"claim":"Expanded the role of LMAN1 beyond secretion by showing it is required for production of infectious arenavirus, coronavirus and filovirus particles via lectin-independent association with viral glycoproteins.","evidence":"siRNA knockdown, co-IP, live-cell imaging and viral infectivity/particle assays across virus families","pmids":["24237698"],"confidence":"High","gaps":["Molecular basis of lectin-independent viral GP association undefined","Host attachment defect mechanism not resolved"]},{"year":2015,"claim":"Added MMP-9 to the LMAN1 cargo repertoire, showing N-glycosylation-dependent interaction and KO-dependent secretion defects.","evidence":"Protein fragment complementation, co-IP and LMAN1 KO secretion assays","pmids":["26150355"],"confidence":"Medium","gaps":["Single lab without reciprocal in vivo validation","MCFD2 involvement not tested"]},{"year":2018,"claim":"Genetic epistasis in MCFD2 vs LMAN1 KO mice revealed an alternative FVIII secretion pathway and shared roles in alpha1-antitrypsin export, refining the relative contributions of the two components.","evidence":"MCFD2 KO and double-KO mice with plasma factor assays and hepatocyte ER analysis","pmids":["29735583"],"confidence":"High","gaps":["Identity of the alternative FVIII pathway unknown","Sex-specific AAT effects unexplained"]},{"year":2019,"claim":"Identified a glycan-independent role for LMAN1 in trafficking neuronal GABAA and 5HT3A receptors, expanding cargo recognition modes beyond lectin binding.","evidence":"siRNA knockdown, Western blot of LMAN1 KO brain, surface trafficking and co-IP with glycan-independence test","pmids":["30791981"],"confidence":"Medium","gaps":["Single lab; receptor-class generality unknown","Structural basis of glycan-independent recognition undefined"]},{"year":2022,"claim":"Demonstrated with CRISPR KO and rescue that the LMAN1-MCFD2 complex transports alpha1-antitrypsin in a glycosylation-site-dependent but MCFD2-independent manner, clarifying cargo-specific requirements.","evidence":"CRISPR KO of LMAN1 and MCFD2, secretion/intracellular assays, rescue and AAT glycosite mutagenesis with co-IP","pmids":["35322856"],"confidence":"High","gaps":["Reconciliation of MCFD2-independence for AAT vs MCFD2-dependence for FVIII not fully mechanistic"]},{"year":2023,"claim":"Challenged the prevailing model by showing LMAN1 carbohydrate binding is dispensable for FV/FVIII transport and that MCFD2 overexpression alone rescues secretion, recasting LMAN1 as a transmembrane shuttle for MCFD2.","evidence":"Multiple LMAN1/MCFD2 KO cell lines with secretion assays, carbohydrate-binding-mutant and MCFD2-overexpression rescue","pmids":["36490287"],"confidence":"Medium","gaps":["Single lab; reconciliation with earlier lectin-dependent FV/FVIII data needed","Whether MCFD2 alone reaches Golgi without LMAN1 unclear"]},{"year":2023,"claim":"Revealed a non-secretory surface function for LMAN1 as a house dust mite allergen receptor that dampens NF-κB signaling via FcRγ and SHP1, identifying an immunomodulatory role.","evidence":"Receptor glycocapture screen, direct binding, NF-κB reporter assay, co-IP and SHP1 recruitment assays","pmids":["36870056"],"confidence":"Medium","gaps":["Single lab; physiological relevance in vivo limited","Relationship between surface pool and secretory cycling unclear"]},{"year":2024,"claim":"Established LMAN1 as a hepatocyte cargo receptor for thrombopoietin, linking it to platelet homeostasis through an MCFD2-independent mechanism.","evidence":"Tissue-specific Lman1 KO mice with platelet/MK counts, plasma TPO, co-IP and intracellular accumulation assays","pmids":["39499573"],"confidence":"High","gaps":["TPO recognition determinant (glycan vs protein) not fully mapped","Why TPO transport is MCFD2-independent unresolved"]},{"year":null,"claim":"It remains unresolved how LMAN1 selects its diverse cargo through both lectin-dependent and glycan-independent modes, and how the relative roles of carbohydrate binding versus MCFD2 are reconciled across different cargo classes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model explaining glycan-dependent vs glycan-independent cargo recognition","Conflicting evidence on whether LMAN1 lectin activity is required for FV/FVIII transport","Identity of the alternative MCFD2-independent FVIII secretion route unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[7,9,21,33,34,43]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[16,25,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,9,15]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,42]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,9,21,40]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,6,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,18,40]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,32,37]}],"complexes":["LMAN1-MCFD2 cargo receptor complex","ERGIC-53 hexamer"],"partners":["MCFD2","SEC23","SURF4","ERP44","UBXD1","VIPL","FCRΓ","SUMF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49257","full_name":"Protein ERGIC-53","aliases":["ER-Golgi intermediate compartment 53 kDa protein","Gp58","Intracellular mannose-specific lectin MR60","Lectin mannose-binding 1"],"length_aa":510,"mass_kda":57.5,"function":"Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins","subcellular_location":"Endoplasmic reticulum-Golgi intermediate compartment membrane; Golgi apparatus membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P49257/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMAN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000074695","cell_line_id":"CID000923","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"MCFD2","stoichiometry":10.0},{"gene":"COPZ1","stoichiometry":0.2},{"gene":"GORASP2","stoichiometry":0.2},{"gene":"RMDN3","stoichiometry":0.2},{"gene":"VPS13C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000923","total_profiled":1310},"omim":[{"mim_id":"620436","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 9; TMED9","url":"https://www.omim.org/entry/620436"},{"mim_id":"617852","title":"SEC23-INTERACTING PROTEIN; SEC23IP","url":"https://www.omim.org/entry/617852"},{"mim_id":"616876","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 5; TMED5","url":"https://www.omim.org/entry/616876"},{"mim_id":"614641","title":"LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 5; LAMP5","url":"https://www.omim.org/entry/614641"},{"mim_id":"613625","title":"FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 2; F5F8D2","url":"https://www.omim.org/entry/613625"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LMAN1"},"hgnc":{"alias_symbol":["MR60","ERGIC-53","ERGIC53","gp58","MCFD1","FMFD1"],"prev_symbol":["F5F8D"]},"alphafold":{"accession":"P49257","domains":[{"cath_id":"2.60.120.200","chopping":"44-273","consensus_level":"high","plddt":95.9003,"start":44,"end":273}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49257","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49257-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49257-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMAN1","jax_strain_url":"https://www.jax.org/strain/search?query=LMAN1"},"sequence":{"accession":"P49257","fasta_url":"https://rest.uniprot.org/uniprotkb/P49257.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49257/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49257"}},"corpus_meta":[{"pmid":"9546392","id":"PMC_9546392","title":"Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9546392","citation_count":353,"is_preprint":false},{"pmid":"10559958","id":"PMC_10559958","title":"The lectin ERGIC-53 is a cargo transport receptor for glycoproteins.","date":"1999","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10559958","citation_count":271,"is_preprint":false},{"pmid":"10652252","id":"PMC_10652252","title":"ERGIC-53 and traffic in the secretory pathway.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10652252","citation_count":268,"is_preprint":false},{"pmid":"9395526","id":"PMC_9395526","title":"The recycling of ERGIC-53 in the early secretory pathway. 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functional readout in two assays (retention and endocytosis), single lab but orthogonal methods\",\n      \"pmids\": [\"8119975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The cytoplasmic domain of ERGIC-53 is required and sufficient for pre-medial-Golgi localization, containing a COOH-terminal dilysine ER-retrieval signal (KKFF) and an adjacent RSQQE targeting determinant; the two C-terminal phenylalanines modulate both signals and are required for full recycling through the ER-ERGIC-cis-Golgi pathway.\",\n      \"method\": \"Domain-swap experiments with CD4 reporter, N-glycosylation/endoglycosidase H resistance assay, immunofluorescence microscopy, site-directed mutagenesis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution via domain swaps plus mutagenesis with multiple readouts, foundational targeting paper\",\n      \"pmids\": [\"7559786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ERGIC-53 is identical to the intracellular mannose-specific lectin MR60 isolated from myelomonocytic cells; sequence homology to leguminous lectins and galectins was established.\",\n      \"method\": \"cDNA cloning, peptide sequence matching, sequence homology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — molecular identity established by cDNA/peptide matching, replicated but no functional assay in this paper\",\n      \"pmids\": [\"7876089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ERGIC-53 is a functional mannose-selective, calcium-dependent lectin. Overexpressed ERGIC-53 binds mannose columns in a calcium-dependent manner; substitution of a conserved asparagine in the putative carbohydrate recognition domain (CRD), or a second CRD-site residue, abolishes mannose binding and co-staining with mannosylated neoglycoprotein.\",\n      \"method\": \"Mannose-affinity chromatography of overexpressed protein, morphological binding assay with mannosylated neoglycoprotein, site-directed mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay plus mutagenesis, replicated in subsequent structural and biochemical work\",\n      \"pmids\": [\"8868475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ERGIC-53 carries a C-terminal cytoplasmic phenylalanine-dependent ER-exit determinant that interacts directly with the COPII coat component Sec23p; the two terminal phenylalanines are essential for ER exit and for this interaction.\",\n      \"method\": \"Site-directed mutagenesis, in vitro peptide binding assay with Sec23p, subcellular trafficking assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of COPII interaction plus mutagenesis, defining mechanism replicated across labs\",\n      \"pmids\": [\"9395526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ERGIC-53 cycles continuously through ER, ERGIC, and cis-Golgi; the major retrograde recycling pathway of ERGIC-53 bypasses the Golgi apparatus, returning directly from ERGIC to ER, as shown by temperature-shift experiments and immunogold electron microscopy.\",\n      \"method\": \"Temperature-shift experiments, immunofluorescence microscopy, immunogold electron microscopy, density-gradient centrifugation in HepG2 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal imaging and biochemical methods, replicated in multiple cell types\",\n      \"pmids\": [\"9788882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mistargeting ERGIC-53 to the ER (by a retention mutant that sequesters endogenous ERGIC-53) specifically impairs secretion of cathepsin C precursor while leaving other lysosomal enzymes and membrane glycoproteins unaffected, establishing that ERGIC-53 recycling is required for efficient transport of a selective subset of glycoproteins.\",\n      \"method\": \"Tetracycline-inducible expression of ER-retention mutant in HeLa cells, metabolic labeling, immunoprecipitation of secreted glycoproteins\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific substrate-level readout, foundational cargo-receptor paper\",\n      \"pmids\": [\"9679138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mutations in ERGIC-53 (null mutations) cause combined deficiency of coagulation factors V and VIII, identifying ERGIC-53 as an ER-to-Golgi molecular chaperone/transport receptor required for secretion of FV and FVIII.\",\n      \"method\": \"Positional cloning, DNA sequence analysis, immunofluorescence and Western blot of patient lymphocytes\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease gene identification by positional cloning confirmed by protein absence in patient cells, replicated widely\",\n      \"pmids\": [\"9546392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ERGIC-53 functions as a cargo transport receptor for glycoproteins: it binds a cathepsin-Z-related glycoprotein in the ER in a carbohydrate- and calcium-dependent manner, and cargo dissociation occurs in the ERGIC. Binding does not require ERGIC-53 oligomerization, but oligomerization is required for ER exit of ERGIC-53 itself.\",\n      \"method\": \"Co-immunoprecipitation, calcium-depletion and glycan-modification experiments, temperature-block assays, mislocalization studies\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with mechanistic dissection of Ca2+/carbohydrate dependence, multiple orthogonal conditions, widely replicated\",\n      \"pmids\": [\"10559958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The sugar-binding ability of ERGIC-53 (MR60) requires a dimeric state: a truncated protein retaining Cys466 (but not Cys475) forms dimers and binds mannosides, whereas a shorter construct lacking both cysteines neither dimerizes nor binds mannose.\",\n      \"method\": \"Expression of recombinant truncated proteins, mannose-column binding, immunoprecipitation/SDS-PAGE oligomerization analysis\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and oligomerization assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"10521535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the carbohydrate recognition domain (CRD) of rat p58/ERGIC-53 determined to 1.46 Å resolution (calcium-free form); the fold resembles leguminous lectins with a beta-sandwich and a negatively charged ligand-binding cleft; a conserved surface patch on the opposite face is implicated in protein-protein interactions and oligomerization.\",\n      \"method\": \"X-ray crystallography at 1.46 Å resolution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional interpretation, independently extended by subsequent structural studies\",\n      \"pmids\": [\"11850423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ER export of ERGIC-53 requires three cooperating determinants: (1) a C-terminal phenylalanine motif for COPII interaction, assisted by a cytoplasmic glutamine; (2) disulfide-bond-stabilized hexamerization dependent on polar and aromatic residues in the transmembrane domain; (3) optimal transmembrane domain length of 21 amino acids. Together these reconstitute full transport activity.\",\n      \"method\": \"Site-directed mutagenesis, endoglycosidase H resistance assay, immunofluorescence, reconstitution with signal-less construct\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis combined with reconstitution in a single rigorous study\",\n      \"pmids\": [\"13130098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the CRD of p58/ERGIC-53 in the calcium-bound form reveals two calcium-binding sites 6 Å apart (one novel, one homologous to plant lectins), large conformational changes in the ligand-binding site upon calcium binding, and absence of the short loop present in plant lectins, consistent with preference for Man8GlcNAc2 glycans at ER exit.\",\n      \"method\": \"X-ray crystallography (calcium-bound form)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure independently confirming and extending the 2002 structure\",\n      \"pmids\": [\"14643651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LMAN1 interacts with coagulation factor VIII in vivo via co-immunoprecipitation; the interaction is mediated by both high-mannose N-linked oligosaccharides in the B domain of FVIII and protein-protein contacts.\",\n      \"method\": \"Co-immunoprecipitation from transfected HeLa and COS-1 cells, glycosylation modification experiments\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with mechanistic follow-up (glycan vs. protein contribution), single lab\",\n      \"pmids\": [\"14629470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"pH-induced conversion of ERGIC-53 triggers glycoprotein cargo release: ERGIC-53 binds mannose efficiently at pH 7.4 (ER pH) but not at slightly lower pH (ERGIC pH); a conserved histidine in the CRD center is required for lectin activity and acts as a molecular pH/Ca2+ sensor. Organelle neutralization impairs cargo dissociation in the ERGIC.\",\n      \"method\": \"In vitro mannose-binding assay at varying pH and Ca2+ concentrations, histidine mutagenesis, acidification of live cells, organelle pH neutralization, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis plus cell-based validation, orthogonal methods in one study\",\n      \"pmids\": [\"14718532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LMAN1 and MCFD2 form a stoichiometric 1:1 complex in cells; MCFD2 is retained in the ER via its interaction with LMAN1. Both LMAN1 and MCFD2 interact specifically with factor VIII (primarily via the B domain) in a calcium-dependent, glycosylation-independent manner. MCFD2 can interact with FVIII independently of LMAN1-MCFD2 complex formation.\",\n      \"method\": \"Co-immunoprecipitation, cross-linking-immunoprecipitation, stoichiometry analysis, Western blot, calcium chelation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with cross-linking, stoichiometry determination, mechanistic dissection with multiple conditions, replicated\",\n      \"pmids\": [\"15886209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ERGIC-53 forms exclusively hexameric complexes in cells, existing in two forms: covalent disulfide-linked and non-covalent SDS-sensitive hexamers assembled from three disulfide-linked dimers via coiled-coil interactions. Neither membrane-proximal cysteine is essential for hexamer formation or intracellular ERGIC distribution.\",\n      \"method\": \"Sucrose gradient sedimentation, chemical cross-linking, non-denaturing gel electrophoresis, subcellular fractionation, cysteine mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods, mutagenesis, single rigorous study\",\n      \"pmids\": [\"16257008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MCFD2 is required for the ERGIC-53-dependent ER export of coagulation factors V and VIII but is dispensable for ERGIC-53 binding to cathepsin Z and cathepsin C; in the absence of ERGIC-53, MCFD2 is secreted rather than retained in the ER, establishing ERGIC-53 as the membrane anchor of the complex.\",\n      \"method\": \"siRNA knockdown of ERGIC-53 and MCFD2, YFP fragment complementation assay in vivo, localization studies\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with specific cargo readouts plus protein-fragment complementation, cargo selectivity defined\",\n      \"pmids\": [\"17010120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Frontal affinity chromatography shows ERGIC-53 binds high-mannose oligosaccharides with low affinity and broad specificity, not distinguishing between monoglucosylated and deglucosylated high-mannose N-glycans; single amino acid substitutions in the CRD can switch the sugar-binding properties.\",\n      \"method\": \"Frontal affinity chromatography with pyridylaminated sugar library, structure-based mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro binding assay with mutagenesis, single lab but rigorous\",\n      \"pmids\": [\"18025080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MCFD2 binding to ERGIC-53 is enhanced when MCFD2 is present; ERGIC-53 sugar binding is enhanced by its interaction with MCFD2 as shown by flow cytometry and surface plasmon resonance; F5F8D patient MCFD2 missense mutations drastically reduce binding affinity to ERGIC-53; the interaction is Ca2+-dependent (weakened below 0.2 mM Ca2+).\",\n      \"method\": \"Flow cytometry with biotinylated soluble ERGIC-53, surface plasmon resonance, endo-H treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative binding assays (SPR + flow cytometry), two orthogonal methods, Ca2+ dependence quantified\",\n      \"pmids\": [\"18056485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERGIC-53 is an intracellular transport receptor for alpha1-antitrypsin (α1-AT): ERGIC-53 binds α1-AT in a carbohydrate- and conformation-dependent manner; ERGIC-53 knockdown and knockout cells show a specific secretion defect of α1-AT that is corrected by ERGIC-53 re-expression.\",\n      \"method\": \"YFP-based protein fragment complementation screening of cDNA library, siRNA knockdown, ERGIC-53 KO cell reconstitution, secretion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including KO rescue, carbohydrate/conformation dependence established\",\n      \"pmids\": [\"18283111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUMF1 interacts with ERGIC-53 in the early secretory pathway; ERGIC-53 favors SUMF1 export from the ER; silencing ERGIC-53 causes proteasomal degradation of SUMF1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing with SUMF1 trafficking and stability assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional silencing experiment, single lab, two methods\",\n      \"pmids\": [\"18508857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Surf4 interacts with ERGIC-53; co-silencing of Surf4 and ERGIC-53 (but not either alone) reduces the number of ERGIC clusters and fragments the Golgi, partially redistributing COPI but not Golgi matrix proteins, establishing that cargo receptors collectively maintain ERGIC and Golgi architecture by controlling COPI recruitment.\",\n      \"method\": \"siRNA knockdown (single and double), co-immunoprecipitation, live imaging of ERGIC stability, immunofluorescence for COPI and Golgi markers, BFA resistance assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockdown plus co-IP and live imaging, multiple orthogonal readouts\",\n      \"pmids\": [\"18287528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal EF-hand domains of MCFD2 are both necessary and sufficient for interaction with LMAN1; these same EF-hand domains also mediate interaction with FV and FVIII but via a site separable from the LMAN1-binding site; Ca2+-induced folding is important for LMAN1 interaction but not for FV/FVIII binding.\",\n      \"method\": \"MCFD2 deletion and missense mutant analysis, co-immunoprecipitation, circular dichroism spectroscopy\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus CD spectroscopy plus co-IP, orthogonal methods defining separate binding sites\",\n      \"pmids\": [\"20007547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The LMAN1 CRD contains distinct, separable binding sites for MCFD2 (N-terminal beta sheet) and for FV/FVIII cargo (Ca2+- and sugar-binding sites); monomeric LMAN1 mutants are defective in ER exit and cannot interact with MCFD2, indicating oligomerization is necessary for cargo receptor function.\",\n      \"method\": \"Mutagenesis of LMAN1 CRD, co-immunoprecipitation, FVIII interaction assays, oligomerization analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis separating binding sites with multiple functional readouts, consistent with crystal structures\",\n      \"pmids\": [\"20817851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the LMAN1-CRD/MCFD2 complex reveals the protein-protein interaction interface; circular dichroism shows that most F5F8D missense mutations in MCFD2 cause global destabilization, while stable mutations map to the LMAN1-binding surface.\",\n      \"method\": \"X-ray crystallography of LMAN1-CRD/MCFD2 complex, circular dichroism of MCFD2 mutants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biophysical characterization of disease mutants\",\n      \"pmids\": [\"20138881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LMAN1-deficient mice exhibit ~50% reductions in plasma FV and FVIII and platelet FV; ER in hepatocytes is slightly distended with accumulation of α1-antitrypsin and GRP78; no significant effect on cathepsin C or Z levels in liver or α1-antitrypsin in plasma under normal conditions.\",\n      \"method\": \"Lman1 knockout mouse analysis, plasma coagulation factor assays, liver histology and EM, protein level analysis by Western blot\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with multiple substrate-specific readouts\",\n      \"pmids\": [\"21795745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UBXD1 interacts with ERGIC-53 via the N-terminal 10 residues of UBXD1 and the C-terminal cytoplasmic tail of ERGIC-53; this interaction requires p97 ATPase activity but not ubiquitin modification; UBXD1 modulates subcellular trafficking of ERGIC-53 including promoting its movement to the cell membrane.\",\n      \"method\": \"LC-MS/MS interactome, co-immunoprecipitation, SILAC proteomic profiling, localization studies, p97/E1 inhibitor experiments\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP confirmed by MS, localization study, p97 inhibitor experiment, single lab\",\n      \"pmids\": [\"22337587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Under ER stress, ERGIC-53 redistributes from broad ER/Golgi distribution to compact Golgi localization; this redistribution is abrogated by co-expression of VIPL; ERGIC-53 co-precipitates with VIPL but not VIP36, indicating VIPL interaction regulates ERGIC-53 localization.\",\n      \"method\": \"Monoclonal antibody generation, immunostaining, flow cytometry, co-immunoprecipitation, UPR induction with tunicamycin\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus localization under defined stress conditions, single lab\",\n      \"pmids\": [\"22821029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of ERGIC-53-CRD complexed with MCFD2 and α1,2-mannotriose reveals that ERGIC-53 can bind the D1 trimannosyl arm in two alternative modes; a single Asp-to-Gly substitution creates a shallower sugar-binding pocket compared to VIP36, enabling ERGIC-53 to accommodate terminal glucose residues.\",\n      \"method\": \"X-ray crystallography of ternary complex (ERGIC-53-CRD/MCFD2/mannotriose)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution ternary crystal structure defining molecular basis of broad sugar specificity\",\n      \"pmids\": [\"24498414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of LMAN1-CRD bound to Man-α-1,2-Man define the central mannose-binding site; mutagenesis identifies His178 and Gly251/252 as critical for FV/FVIII binding; mannobiose binding is relatively pH-independent but sensitive to lowered Ca2+ concentrations, suggesting Ca2+ regulates cargo release.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, in vitro binding assays, pH and Ca2+ titration\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and quantitative binding assays in one study\",\n      \"pmids\": [\"23709226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERGIC-53 is required for production of infectious arenavirus, coronavirus, and filovirus particles; ERGIC-53 associates with viral glycoproteins through a lectin-independent mechanism, traffics to budding sites, and is incorporated into virions; in its absence, GP-containing virus particles form but are non-infectious due to impaired host-cell attachment.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, live-cell imaging, viral infectivity and particle formation assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with specific infectivity readout plus co-IP and imaging, multiple virus families tested\",\n      \"pmids\": [\"24237698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mac-2BP (Mac-2 binding protein) is a novel ERGIC-53 cargo glycoprotein; interaction requires high-mannose-type N-glycan binding by ERGIC-53; ERGIC-53 ER-mistargeting mutant blocks Mac-2BP transport; MCFD2 is also involved in Mac-2BP secretion.\",\n      \"method\": \"GFP fragment complementation cDNA library screen, N-glycan-binding-deficient mutant (N156A), ER-mistargeting mutant (KKAA), glycosylation inhibitors, co-immunoprecipitation\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation screen plus mutant and inhibitor validation, single lab\",\n      \"pmids\": [\"23550150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LMAN1 interacts with N-glycosylated MMP-9 in the ER and is required for efficient MMP-9 secretion; N-glycosylation-deficient MMP-9 is secretion-compromised; LMAN1 knockout cells show reduced MMP-9 secretion.\",\n      \"method\": \"Protein fragment complementation assay, co-immunoprecipitation, LMAN1 KO cell secretion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — complementation assay plus co-IP plus KO functional assay, single lab, two orthogonal approaches\",\n      \"pmids\": [\"26150355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MCFD2-deficient mice have lower plasma FV and FVIII than LMAN1-deficient mice; doubly deficient mice match LMAN1-deficient levels, suggesting an alternative FVIII secretion pathway exists. Both LMAN1 and MCFD2 deficiency cause decreased plasma α1-antitrypsin in male mice and comparable ER accumulation of AAT in hepatocytes.\",\n      \"method\": \"Mouse gene targeting (MCFD2 KO), plasma coagulation factor assays, comparison of singly and doubly deficient mice, hepatocyte ER analysis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double KO genetic epistasis with multiple quantitative cargo readouts\",\n      \"pmids\": [\"29735583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LMAN1 promotes surface trafficking of GABAAR β3 subunits in mouse hypothalamic neurons; LMAN1 KO mice show decreased total protein levels of 5HT3A receptors and GABAAR γ2 subunits; LMAN1 interacts with GABAARs in a glycan-independent manner; LMAN1 KO upregulates ERp44 without changing calnexin.\",\n      \"method\": \"siRNA knockdown, Western blot of brain homogenates from LMAN1 KO mice, surface trafficking assay, co-immunoprecipitation with glycan-independence test\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus co-IP with mechanistic follow-up, single lab, novel substrate class\",\n      \"pmids\": [\"30791981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBV exploits ERGIC-53 for viral particle propagation; ERGIC-53 interacts with the N146-glycan of the HBV envelope in a productive, lectin-dependent manner; ERGIC-53 silencing blocks infectious viral particle exit but not subviral particle exit; ERGIC-53 acts after nucleocapsid envelopment in conjunction with ESCRT components.\",\n      \"method\": \"siRNA silencing, molecular interaction studies, cell imaging in HBV-expressing liver cells, particle infectivity assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — silencing with specific viral vs. subviral particle readout, interaction mapped to specific glycan, single lab\",\n      \"pmids\": [\"32806600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Multiple crystal forms of the ERGIC-53-CRD/MCFD2 complex at up to 1.60 Å resolution reveal that MCFD2 (but not ERGIC-53-CRD) exhibits significant conformational plasticity potentially enabling accommodation of diverse polypeptide cargo ligands.\",\n      \"method\": \"X-ray crystallography (multiple crystal forms, 1.60 Å best resolution)\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple crystal structures revealing conformational dynamics, single lab\",\n      \"pmids\": [\"32356523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERp44 binds ERGIC-53 in the ER to negotiate preferential loading into COPII vesicles; silencing ERGIC-53 causes secretion of Prdx4 (an ERp44-retained client), establishing that ERGIC-53 couples transport of cargo and quality-control inspector proteins.\",\n      \"method\": \"Co-immunoprecipitation, ERGIC-53 siRNA silencing with Prdx4 secretion readout, 4-phenylbutyrate COPII competition\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus knockdown with specific cargo readout, mechanistic model with pharmacological validation, single lab\",\n      \"pmids\": [\"33763635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The LMAN1-MCFD2 complex is a cargo receptor for AAT ER-to-Golgi transport: LMAN1 and MCFD2 KO HepG2 and HEK293T cells show reduced AAT secretion and elevated intracellular AAT due to delayed ER-to-Golgi transport; rescue requires wild-type but not mutant proteins; elimination of the second glycosylation site of AAT abolishes LMAN1-dependent secretion; AAT interaction with LMAN1 is independent of MCFD2.\",\n      \"method\": \"CRISPR KO of LMAN1 and MCFD2, secretion assays, intracellular AAT quantification, rescue with wild-type and mutant proteins, glycosylation site mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with rescue, mutagenesis of cargo glycosylation site, co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"35322856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMAN1 carbohydrate binding is not essential for FV/FVIII transport; overexpression of MCFD2 alone (wild-type or mutant) rescues FV/FVIII secretion in LMAN1-deficient cells, suggesting MCFD2 performs cargo binding/transport and LMAN1 primarily functions as a transmembrane shuttling carrier for MCFD2.\",\n      \"method\": \"Multiple LMAN1/MCFD2 KO cell lines, FV/FVIII secretion assays, carbohydrate-binding mutant rescue, MCFD2 overexpression rescue\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines with rescue experiments and carbohydrate binding mutants, single lab, challenges existing model\",\n      \"pmids\": [\"36490287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMAN1 directly binds house dust mite (HDM) allergens on the surface of dendritic cells and airway epithelial cells; LMAN1 overexpression downregulates NF-κB signaling in response to HDM or inflammatory cytokines; HDM promotes LMAN1 binding to FcRγ and recruitment of SHP1.\",\n      \"method\": \"Receptor glycocapture screen, direct binding verification, overexpression NF-κB reporter assay, co-immunoprecipitation (LMAN1-FcRγ), SHP1 recruitment assay, in vivo localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple binding and signaling assays, single lab, novel surface receptor function\",\n      \"pmids\": [\"36870056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LMAN1 is a cargo receptor for thrombopoietin (TPO): hepatocyte-specific (but not hematopoietic) LMAN1 deletion causes thrombocytopenia with reduced plasma TPO despite normal Tpo mRNA; TPO co-immunoprecipitates with LMAN1; TPO accumulates intracellularly in LMAN1-deleted cells; TPO secretion is MCFD2-independent.\",\n      \"method\": \"Conditional hepatocyte-specific and hematopoietic-specific Lman1 KO mice, platelet and MK quantification, plasma TPO measurement, co-immunoprecipitation, intracellular TPO accumulation assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO mice with specific cargo (TPO) readout, co-IP, intracellular accumulation, MCFD2-independence established\",\n      \"pmids\": [\"39499573\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LMAN1 (ERGIC-53) is a hexameric type I transmembrane lectin that cycles between the ER, ERGIC, and cis-Golgi via COPII-mediated anterograde transport (driven by a C-terminal FF motif interacting with Sec23/24) and COPI-mediated retrograde retrieval (driven by a dilysine KKXX motif); in the ER lumen it functions as a cargo receptor by binding high-mannose N-glycans on a select subset of secretory glycoproteins—including coagulation factors V and VIII, α1-antitrypsin, cathepsins C and Z, MMP-9, TPO, and neuroreceptors—in a calcium- and pH-dependent manner, releasing cargo in the more acidic ERGIC; for FV/FVIII export it forms a 1:1 complex with the soluble EF-hand protein MCFD2, which provides an additional polypeptide-recognition surface for these coagulation factors, while LMAN1 itself primarily serves as the transmembrane carrier shuttling MCFD2; loss-of-function mutations in LMAN1 cause the bleeding disorder combined deficiency of factors V and VIII (F5F8D).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMAN1 (ERGIC-53) is a hexameric type I transmembrane lectin that operates as a glycoprotein cargo receptor in the early secretory pathway, cycling continuously between the ER, ERGIC, and cis-Golgi [#6, #17]. Its short cytoplasmic tail encodes the dual trafficking logic of this cycle: a C-terminal phenylalanine motif that binds the COPII coat component Sec23 to drive ER exit, and a dilysine (KKXX) motif that mediates retrograde retrieval and, upon surface escape, lysine-dependent endocytosis [#1, #5]. Full ER export is reconstituted by three cooperating determinants—the COPII phenylalanine signal, disulfide- and coiled-coil-stabilized hexamerization, and an optimal transmembrane domain length [#12]. Within the ER lumen, its leguminous-lectin-fold carbohydrate recognition domain binds high-mannose N-glycans with broad, low-affinity specificity in a calcium-dependent manner [#4, #11, #19], and a conserved CRD histidine acts as a pH/Ca2+ sensor so that cargo is captured at ER pH and released in the more acidic ERGIC [#15]. Through this mechanism LMAN1 selectively promotes ER-to-Golgi transport of a defined subset of secretory glycoproteins, including cathepsin C and cathepsin Z, alpha1-antitrypsin, Mac-2BP, MMP-9, and thrombopoietin [#7, #9, #21, #33, #34, #43]. For coagulation factors V and VIII, LMAN1 forms a stoichiometric 1:1 complex with the soluble EF-hand protein MCFD2, which it anchors in the ER and which contributes an additional polypeptide-recognition surface; the MCFD2- and cargo/sugar-binding sites on the CRD are structurally separable [#16, #25, #26, #30]. Loss-of-function mutations in LMAN1 cause the autosomal recessive bleeding disorder combined deficiency of coagulation factors V and VIII (F5F8D) [#8]. Beyond its secretory role, LMAN1 is exploited by multiple enveloped viruses for production of infectious particles [#32, #37] and functions at the cell surface as a receptor for house dust mite allergens that dampens NF-\\u03baB signaling [#42].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that LMAN1's cytoplasmic dilysine motif is the operational signal for pre-Golgi retention, answering how the protein is confined to the early secretory pathway.\",\n      \"evidence\": \"Site-directed mutagenesis of the KKXX lysines with retention and endocytosis assays in COS cells\",\n      \"pmids\": [\"8119975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the retrograde coat machinery (COPI) recognizing the motif\", \"Surface endocytosis was an overexpression artifact, not the physiological route\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the cytoplasmic domain as necessary and sufficient for cis-Golgi recycling localization and identified an adjacent phenylalanine determinant, resolving the bidirectional targeting code.\",\n      \"evidence\": \"CD4 reporter domain-swap experiments with endoglycosidase H resistance and immunofluorescence readouts\",\n      \"pmids\": [\"7559786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Anterograde coat partner of the phenylalanine motif not yet identified\", \"Luminal cargo-binding function not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated that LMAN1 is a functional mannose-selective, calcium-dependent lectin, providing the molecular basis for glycoprotein cargo recognition.\",\n      \"evidence\": \"Mannose-affinity chromatography of overexpressed protein plus CRD-residue mutagenesis abolishing binding\",\n      \"pmids\": [\"8868475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological cargo glycoproteins not yet identified\", \"Glycan specificity not quantified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed the C-terminal phenylalanine ER-exit determinant binds COPII Sec23 directly, defining the anterograde transport mechanism.\",\n      \"evidence\": \"In vitro peptide binding assay with Sec23p plus mutagenesis and trafficking readouts\",\n      \"pmids\": [\"9395526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address Sec24 cargo-adaptor contribution\", \"Oligomerization requirement for exit not yet established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Connected LMAN1 to human disease by showing null mutations cause combined factor V and VIII deficiency, establishing its physiological role as an FV/FVIII transport receptor.\",\n      \"evidence\": \"Positional cloning and sequencing in F5F8D patients with protein-absence confirmation in patient cells\",\n      \"pmids\": [\"9546392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of FV/FVIII recognition not defined\", \"Did not explain why only FV and FVIII are affected\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated cargo selectivity by showing that ER mistargeting of LMAN1 impairs cathepsin C secretion specifically, establishing the cargo-receptor concept for a defined glycoprotein subset.\",\n      \"evidence\": \"Inducible ER-retention mutant in HeLa cells with metabolic labeling and secretion immunoprecipitation\",\n      \"pmids\": [\"9679138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cargo binding not shown in this study\", \"Full cargo repertoire unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided direct mechanistic proof that LMAN1 binds glycoprotein cargo in the ER in a carbohydrate- and calcium-dependent manner and releases it in the ERGIC, separating binding from oligomerization requirements.\",\n      \"evidence\": \"Co-immunoprecipitation of a cathepsin-Z-related glycoprotein with calcium-depletion, glycan-modification and temperature-block assays\",\n      \"pmids\": [\"10559958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for ERGIC release not yet defined\", \"Stoichiometry of cargo capture unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Solved the CRD crystal structure, revealing a leguminous-lectin fold with a ligand-binding cleft and an oligomerization patch, framing the structural basis of lectin and protein-protein function.\",\n      \"evidence\": \"X-ray crystallography of rat CRD at 1.46 \\u00c5 (calcium-free)\",\n      \"pmids\": [\"11850423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calcium-bound conformation not captured\", \"Glycan-bound complex not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Captured the calcium-bound CRD, showing two calcium sites and ligand-site conformational changes consistent with high-mannose glycan preference, explaining calcium-dependent cargo capture.\",\n      \"evidence\": \"X-ray crystallography of the calcium-bound CRD form\",\n      \"pmids\": [\"14643651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how calcium loss drives cargo release in cells\", \"pH contribution not addressed structurally\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined three cooperating ER-export determinants—COPII phenylalanine signal, disulfide/coiled-coil hexamerization, and transmembrane length—reconstituting full transport competence.\",\n      \"evidence\": \"Systematic mutagenesis with endoglycosidase H resistance and reconstitution of a signal-less construct\",\n      \"pmids\": [\"13130098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address luminal cargo loading during assembly\", \"Retrograde KKXX coupling not examined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a pH/Ca2+-sensing CRD histidine as the molecular switch that releases cargo in the slightly acidic ERGIC, resolving the directionality of the capture-release cycle.\",\n      \"evidence\": \"In vitro mannose-binding at varying pH/Ca2+, histidine mutagenesis and live-cell organelle neutralization with co-IP\",\n      \"pmids\": [\"14718532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile pH sensitivity differences seen with mannobiose in later work\", \"In vivo pH gradient values inferred indirectly\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the hexameric quaternary architecture (three disulfide-linked dimers via coiled coils), defining the functional oligomeric unit of the receptor.\",\n      \"evidence\": \"Sucrose gradients, cross-linking, non-denaturing gels and cysteine mutagenesis\",\n      \"pmids\": [\"16257008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of covalent vs non-covalent hexamers to cargo transport not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovered the stoichiometric 1:1 LMAN1-MCFD2 complex and showed LMAN1 retains MCFD2 in the ER, revealing a two-component receptor for FVIII binding.\",\n      \"evidence\": \"Reciprocal co-IP, cross-linking, stoichiometry analysis and calcium-chelation experiments\",\n      \"pmids\": [\"15886209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative cargo-binding contributions of LMAN1 vs MCFD2 not yet dissected\", \"Binding-site locations on each protein undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed MCFD2 is specifically required for FV/FVIII export but dispensable for cathepsin binding, and that LMAN1 anchors MCFD2, defining cargo-class-specific division of labor.\",\n      \"evidence\": \"siRNA knockdown of LMAN1 and MCFD2 with YFP fragment complementation and localization in vivo\",\n      \"pmids\": [\"17010120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether MCFD2 alone can bind/transport cargo\", \"Mechanism of cargo discrimination unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Quantified LMAN1 glycan specificity as broad, low-affinity high-mannose binding tunable by single CRD substitutions, refining the lectin recognition model.\",\n      \"evidence\": \"Frontal affinity chromatography with a pyridylaminated sugar library plus structure-based mutagenesis\",\n      \"pmids\": [\"18025080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link specific glycan structures to particular cargo proteins in cells\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated cooperative, calcium-dependent LMAN1-MCFD2 binding and that F5F8D MCFD2 missense mutations weaken the interaction, mechanistically linking complex assembly to disease.\",\n      \"evidence\": \"Flow cytometry with biotinylated soluble LMAN1 and surface plasmon resonance\",\n      \"pmids\": [\"18056485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic interface\", \"Effect on cargo transport rates not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified alpha1-antitrypsin as a conformation- and carbohydrate-dependent LMAN1 cargo via an unbiased complementation screen with KO rescue, broadening the physiological cargo set.\",\n      \"evidence\": \"YFP fragment complementation cDNA screen, siRNA knockdown and KO cell reconstitution secretion assays\",\n      \"pmids\": [\"18283111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MCFD2 involvement in AAT transport not yet tested\", \"Specific AAT glycosite not mapped here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that cargo receptors collectively maintain ERGIC and Golgi architecture by controlling COPI recruitment, placing LMAN1 in a redundant transport-receptor network with Surf4.\",\n      \"evidence\": \"Single and double siRNA knockdown with live imaging, co-IP and COPI/Golgi marker immunofluorescence\",\n      \"pmids\": [\"18287528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect contribution to COPI recruitment unresolved\", \"Whether LMAN1 and Surf4 share cargo not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped MCFD2's C-terminal EF-hand domains as both necessary and sufficient for LMAN1 binding, with a separable site for FV/FVIII, refining the architecture of the two-component receptor.\",\n      \"evidence\": \"MCFD2 deletion/missense mutant co-IP plus circular dichroism spectroscopy\",\n      \"pmids\": [\"20007547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution interface not yet solved here\", \"Calcium dependence of cargo vs LMAN1 binding only partially separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localized separable MCFD2- and cargo/sugar-binding sites on the LMAN1 CRD and showed oligomerization is required for both ER exit and MCFD2 binding, integrating structure with function.\",\n      \"evidence\": \"CRD mutagenesis with co-IP, FVIII interaction and oligomerization assays, plus crystal structure of the CRD/MCFD2 complex with CD of disease mutants\",\n      \"pmids\": [\"20817851\", \"20138881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan-bound ternary structure not yet captured\", \"Why most F5F8D MCFD2 mutations destabilize rather than block binding still being worked out\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established an in vivo LMAN1 KO mouse showing ~50% FV/FVIII reductions and ER accumulation of alpha1-antitrypsin, validating physiological cargo relationships in a whole organism.\",\n      \"evidence\": \"Lman1 knockout mouse plasma factor assays, liver histology/EM and Western blot\",\n      \"pmids\": [\"21795745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partial (not complete) FV/FVIII loss implied redundancy\", \"Cathepsin levels unaffected, leaving cargo hierarchy unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided structural and biochemical bases for broad sugar specificity and FV/FVIII recognition, including a ternary glycan complex and identification of critical CRD residues.\",\n      \"evidence\": \"X-ray crystallography of CRD/MCFD2/mannotriose and CRD/Man-\\u03b1-1,2-Man complexes with mutagenesis and pH/Ca2+ titration\",\n      \"pmids\": [\"24498414\", \"23709226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepant pH dependence between sugar species not fully reconciled\", \"Direct cargo-glycan co-structures absent\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the role of LMAN1 beyond secretion by showing it is required for production of infectious arenavirus, coronavirus and filovirus particles via lectin-independent association with viral glycoproteins.\",\n      \"evidence\": \"siRNA knockdown, co-IP, live-cell imaging and viral infectivity/particle assays across virus families\",\n      \"pmids\": [\"24237698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of lectin-independent viral GP association undefined\", \"Host attachment defect mechanism not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Added MMP-9 to the LMAN1 cargo repertoire, showing N-glycosylation-dependent interaction and KO-dependent secretion defects.\",\n      \"evidence\": \"Protein fragment complementation, co-IP and LMAN1 KO secretion assays\",\n      \"pmids\": [\"26150355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal in vivo validation\", \"MCFD2 involvement not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic epistasis in MCFD2 vs LMAN1 KO mice revealed an alternative FVIII secretion pathway and shared roles in alpha1-antitrypsin export, refining the relative contributions of the two components.\",\n      \"evidence\": \"MCFD2 KO and double-KO mice with plasma factor assays and hepatocyte ER analysis\",\n      \"pmids\": [\"29735583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the alternative FVIII pathway unknown\", \"Sex-specific AAT effects unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a glycan-independent role for LMAN1 in trafficking neuronal GABAA and 5HT3A receptors, expanding cargo recognition modes beyond lectin binding.\",\n      \"evidence\": \"siRNA knockdown, Western blot of LMAN1 KO brain, surface trafficking and co-IP with glycan-independence test\",\n      \"pmids\": [\"30791981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; receptor-class generality unknown\", \"Structural basis of glycan-independent recognition undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated with CRISPR KO and rescue that the LMAN1-MCFD2 complex transports alpha1-antitrypsin in a glycosylation-site-dependent but MCFD2-independent manner, clarifying cargo-specific requirements.\",\n      \"evidence\": \"CRISPR KO of LMAN1 and MCFD2, secretion/intracellular assays, rescue and AAT glycosite mutagenesis with co-IP\",\n      \"pmids\": [\"35322856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of MCFD2-independence for AAT vs MCFD2-dependence for FVIII not fully mechanistic\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Challenged the prevailing model by showing LMAN1 carbohydrate binding is dispensable for FV/FVIII transport and that MCFD2 overexpression alone rescues secretion, recasting LMAN1 as a transmembrane shuttle for MCFD2.\",\n      \"evidence\": \"Multiple LMAN1/MCFD2 KO cell lines with secretion assays, carbohydrate-binding-mutant and MCFD2-overexpression rescue\",\n      \"pmids\": [\"36490287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reconciliation with earlier lectin-dependent FV/FVIII data needed\", \"Whether MCFD2 alone reaches Golgi without LMAN1 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-secretory surface function for LMAN1 as a house dust mite allergen receptor that dampens NF-\\u03baB signaling via FcR\\u03b3 and SHP1, identifying an immunomodulatory role.\",\n      \"evidence\": \"Receptor glycocapture screen, direct binding, NF-\\u03baB reporter assay, co-IP and SHP1 recruitment assays\",\n      \"pmids\": [\"36870056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; physiological relevance in vivo limited\", \"Relationship between surface pool and secretory cycling unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established LMAN1 as a hepatocyte cargo receptor for thrombopoietin, linking it to platelet homeostasis through an MCFD2-independent mechanism.\",\n      \"evidence\": \"Tissue-specific Lman1 KO mice with platelet/MK counts, plasma TPO, co-IP and intracellular accumulation assays\",\n      \"pmids\": [\"39499573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TPO recognition determinant (glycan vs protein) not fully mapped\", \"Why TPO transport is MCFD2-independent unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how LMAN1 selects its diverse cargo through both lectin-dependent and glycan-independent modes, and how the relative roles of carbohydrate binding versus MCFD2 are reconciled across different cargo classes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model explaining glycan-dependent vs glycan-independent cargo recognition\", \"Conflicting evidence on whether LMAN1 lectin activity is required for FV/FVIII transport\", \"Identity of the alternative MCFD2-independent FVIII secretion route unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [7, 9, 21, 33, 34, 43]},\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [4, 11, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [16, 25, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 9, 15]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 42]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 9, 21, 40]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 6, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 18, 40]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 32, 37]}\n    ],\n    \"complexes\": [\"LMAN1-MCFD2 cargo receptor complex\", \"ERGIC-53 hexamer\"],\n    \"partners\": [\"MCFD2\", \"Sec23\", \"Surf4\", \"ERp44\", \"UBXD1\", \"VIPL\", \"FcR\\u03b3\", \"SUMF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}