{"gene":"CLEC4M","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"Crystal structures of the carbohydrate-recognition domains (CRDs) of DC-SIGN and DC-SIGNR bound to oligosaccharide revealed that both receptors selectively recognize endogenous high-mannose oligosaccharides through their CRDs in a calcium-dependent manner, and binding studies confirmed this selectivity.","method":"X-ray crystallography of CRD-oligosaccharide complexes combined with binding studies","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional binding validation, independently replicated by multiple subsequent structural studies","pmids":["11739956"],"is_preprint":false},{"year":2001,"finding":"The extracellular domain of DC-SIGNR (and DC-SIGN) forms a tetramer stabilized by an alpha-helical stalk (neck region). The CRDs bind Man9GlcNAc2 oligosaccharide with 17-fold higher affinity than mannose alone, and affinity for a glycopeptide bearing two such oligosaccharides is increased a further 5- to 25-fold, demonstrating multivalent/oligomeric binding.","method":"Chemical cross-linking, equilibrium ultracentrifugation, circular dichroism, binding assays with recombinant fragments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with multiple orthogonal biophysical methods, replicated by subsequent structural studies","pmids":["11384997"],"is_preprint":false},{"year":2001,"finding":"DC-SIGNR binds to multiple strains of HIV-1, HIV-2, and SIV and transmits these viruses to T cell lines and PBMCs in trans; binding is dependent on carbohydrate recognition. DC-SIGNR is expressed on sinusoidal endothelial cells in liver, lymph node sinuses, and placental villi.","method":"Cell-based trans-infection assay, carbohydrate competition, immunostaining","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional trans-infection assay with carbohydrate-dependence controls, replicated by multiple independent labs","pmids":["11226297"],"is_preprint":false},{"year":2004,"finding":"Unlike DC-SIGN (which mediates endocytosis and releases ligand at endosomal pH as a recycling receptor), DC-SIGNR does not release ligand at low pH and does not mediate endocytosis, functioning only as an adhesion receptor with a restricted ligand-binding profile. DC-SIGN and DC-SIGNR also have distinct ligand-binding properties: only DC-SIGN binds blood group antigens including fucosylated structures; both bind high-mannose oligosaccharides. A single amino acid difference (Val351 in DC-SIGN vs. Ser363 in DC-SIGNR) in the CRD determines fucose-binding specificity.","method":"Glycan array screening, structural analysis, mutagenesis, pH-dependent ligand-release assays, endocytosis assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (glycan array, mutagenesis, structure, functional assays) in a single rigorous study","pmids":["15195147"],"is_preprint":false},{"year":2004,"finding":"CD209L/L-SIGN (CLEC4M) acts as an alternative receptor for SARS-CoV entry, mediating susceptibility to SARS-CoV infection in otherwise non-permissive CHO cells when the CD209L cDNA is transfected. L-SIGN is expressed in human lung type II alveolar cells and endothelial cells.","method":"cDNA library screen, retroviral pseudotype infection assay, RT-PCR for viral replication, transfection and infection of CHO cells, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct receptor identification by cDNA rescue in non-permissive cells, confirmed with authentic virus, replicated by independent labs","pmids":["15496474"],"is_preprint":false},{"year":2004,"finding":"The extended neck region of DC-SIGNR stabilizes tetramers; regions near the N-terminus are needed for tetramer stability whereas the portion adjacent to the CRD is sufficient for dimer formation. Crystal structures of truncated DC-SIGNR show CRDs are flexibly linked to the neck, which has alpha-helical segments interspersed with non-helical regions. Cross-linking of full-length receptors in fibroblasts confirms the tetrameric state.","method":"Chemical cross-linking of full-length receptor in fibroblasts, hydrodynamic analysis, X-ray crystallography of truncated constructs, differential scanning calorimetry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with multiple biophysical methods and cell-based confirmation","pmids":["15509576"],"is_preprint":false},{"year":2004,"finding":"L-SIGN and DC-SIGN capture HCV by binding to HCV envelope glycoprotein E2 via high-mannose N-glycans (blocked by mannan, EGTA, and anti-CRD antibodies), and SIGN-HCV pseudovirus complexes are internalized and then transinfect adjacent human liver cells; virus capture and transinfection require internalization of the SIGN-HCV complex.","method":"HCV pseudovirus entry assay, co-culture transinfection assay, inhibitor studies (mannan, EGTA, antibodies)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional trans-infection assay with multiple inhibitor controls, replicated across multiple labs","pmids":["15371595"],"is_preprint":false},{"year":2004,"finding":"The molecular basis for DC-SIGN vs. L-SIGN difference in Lewis antigen binding is a single amino acid: Val351 in DC-SIGN creates a hydrophobic pocket for Fucα1,3/4-GlcNAc interaction, while the equivalent Ser363 in L-SIGN creates a hydrophilic pocket preventing Lex (Fucα1,3-GlcNAc) but supporting Lea/Leb binding. The S363V gain-of-function L-SIGN mutant acquired Lex binding.","method":"Binding assays with neoglycoconjugates, site-directed mutagenesis, molecular modeling and docking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional binding assays and structural modeling in single study","pmids":["15184372"],"is_preprint":false},{"year":2004,"finding":"L-SIGN (expressed by THP-1 cells) internalizes HCV particles into non-lysosomal compartments, protecting them from lysosomal degradation, in a manner similar to DC-SIGN. This suggests L-SIGN on liver sinusoidal endothelial cells captures HCV from blood and transmits it to hepatocytes.","method":"Cell-based internalization assays, confocal microscopy of intracellular HCV trafficking, antibody blocking","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of internalization route, single lab, two complementary methods","pmids":["15254204"],"is_preprint":false},{"year":2005,"finding":"Homozygous L-SIGN (CLEC4M) cells show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and lower capacity for trans-infection compared to heterozygous cells, demonstrating that CLEC4M neck-repeat homozygosity confers a protective role during SARS infection.","method":"Genetic association study combined with cell-based binding assays, viral degradation assays, and trans-infection assays on homozygous vs. heterozygous cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional cell-based assays linked to genotype, multiple mechanistic readouts","pmids":["16369534"],"is_preprint":false},{"year":2005,"finding":"The crystal structure of DC-SIGNR with its last repeat region reveals conformational changes in calcium/carbohydrate coordination loops of the CRD, an additional disulfide bond between N and C termini of the CRD, and a helical conformation for the last repeat, enabling generation of a tetramer model for DC-SIGN/R.","method":"X-ray crystallography, homology modeling","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with detailed structural analysis, single lab","pmids":["15784257"],"is_preprint":false},{"year":2006,"finding":"DC-SIGNR promotes West Nile virus (WNV) infection much more efficiently than DC-SIGN; this differential utilization maps to the carbohydrate recognition domain of DC-SIGNR via chimera analysis, and WNV virions bind DC-SIGNR with much greater affinity than DC-SIGN.","method":"Chimeric receptor analysis, infection assays in transfected cells, virus binding affinity measurements","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — chimera domain-swap experiments with quantitative binding and infection assays, single lab","pmids":["16415006"],"is_preprint":false},{"year":2006,"finding":"DC-SIGNR neck-domain polymorphic alleles with five and six repeat units bind viral glycoproteins, augment viral infection, and tetramerize with comparable efficiency to the wild-type seven-repeat allele. Coexpression of wt and five-repeat alleles does not decrease pathogen capture, indicating potential hetero-oligomers do not impair function.","method":"Viral infection enhancement assays, tetramerization assays, coexpression experiments","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts, single lab","pmids":["16413044"],"is_preprint":false},{"year":2006,"finding":"Only the smallest (shortest neck) polymorphic form of DC-SIGNR is defective in homotetramer assembly, whereas DC-SIGNR polypeptides of different neck lengths form stable heterotetramers detectable in transfected fibroblasts.","method":"Chemical cross-linking, analytical ultracentrifugation, affinity-tagging approach, transfected fibroblast expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods plus cell-based confirmation, single lab","pmids":["16621794"],"is_preprint":false},{"year":2007,"finding":"Seven specific asparagine-linked glycosylation sites on the SARS-CoV spike protein (N109, N118, N119, N158, N227, N589, N699) are critical for DC/L-SIGN-mediated virus entry; these sites are distinct from the ACE2-binding domain, and both DC-SIGN and L-SIGN can function as independent entry receptors for SARS-CoV.","method":"Site-directed mutagenesis of glycosylation sites on spike protein, pseudovirus infection assays in DC/L-SIGN-expressing cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic site-directed mutagenesis combined with functional infection assays, single lab","pmids":["17715238"],"is_preprint":false},{"year":2007,"finding":"Der p 1 cysteine protease cleaves DC-SIGNR from the cell surface at a major cleavage site; loss of DC-SIGNR from the cell surface reduces binding of the endogenous ligand ICAM-3.","method":"In silico substrate prediction (PoPS), cell-surface cleavage assays, purified recombinant protein digestion, N-terminal sequencing, MALDI mass spectrometry, ICAM-3 binding assay","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteolytic cleavage identified by MS and sequencing with functional consequence shown, single lab","pmids":["17250696"],"is_preprint":false},{"year":2008,"finding":"DC-SIGNR (co-expressed with LSECtin on liver, lymph node, and bone marrow sinusoidal endothelial cells) binds soluble Ebola virus glycoprotein with affinity comparable to LSECtin. Unlike DC-SIGN, DC-SIGNR does not efficiently capture HIV-1 particles (despite binding soluble HIV-1 GP), and exposure to low-pH releases ligand from DC-SIGNR (but not from LSECtin).","method":"Binding affinity measurements, virion capture assays, pH-dependent ligand release assays, co-expression immunostaining","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays, single lab","pmids":["18083206"],"is_preprint":false},{"year":2009,"finding":"Neck domains of DC-SIGNR expressed in isolation form tetramers autonomously without the CRDs, and stability of tetramers depends on neck domain sequences. Neck and CRD domains are organized independently. Polymorphic DC-SIGNR forms with fewer repeats show modestly reduced stability; DC-SIGNR tetramers are significantly more stable than DC-SIGN tetramers.","method":"Gel filtration, differential scanning calorimetry, circular dichroism, isolated neck domain expression","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods on isolated domain, single lab","pmids":["19249311"],"is_preprint":false},{"year":2009,"finding":"The neck region of DC-SIGNR forms a segmented helical structure consisting of four-helix bundles connected by short non-helical linkers, as determined by crystallography of a multi-repeat fragment. The CRDs are flexibly linked to the neck. An almost-complete model of the DC-SIGNR extracellular domain was derived.","method":"X-ray crystallography of multi-repeat neck fragment","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of multi-repeat domain, single lab","pmids":["19835887"],"is_preprint":false},{"year":2009,"finding":"DC-SIGN transmits HIV-1 to target cells while L-SIGN does not, due to differences in the carbohydrate recognition domain (CRD). Replacement of the DC-SIGN CRD with that of L-SIGN abolishes virus binding and transmission; conversely, the DC-SIGN CRD confers HIV-1 binding/transmission to L-SIGN chimeras. Trp-258 in the DC-SIGN CRD is essential for HIV-1 transmission, and K270W mutation alone in L-SIGN is insufficient.","method":"DC-SIGN/L-SIGN chimera analysis in Raji B cells, site-directed mutagenesis, trans-infection assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain-swap chimeras plus point mutagenesis with functional readout, single lab","pmids":["19833723"],"is_preprint":false},{"year":2010,"finding":"DC-SIGN and L-SIGN can mediate sialic acid-independent attachment and entry of influenza A viruses (H3N2) in sialic acid-deficient Lec2 CHO cells, dependent on mannose-rich N-linked glycans on the virus and Ca2+-dependent lectin activity. H1N1 strains with low mannose-rich glycans are inefficient at infecting DC-SIGN/L-SIGN-expressing cells.","method":"Infection assay in sialic-acid-deficient CHO cells expressing DC-SIGN or L-SIGN, mannan competition, Ca2+ chelation, bacterial neuraminidase controls","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — definitive receptor assay using SA-deficient cells with multiple controls, single lab","pmids":["21191006"],"is_preprint":false},{"year":2011,"finding":"RSV attachment glycoprotein G binds both DC-SIGN and L-SIGN (measured by surface plasmon resonance), and this interaction triggers ERK1 and ERK2 phosphorylation in DC/L-SIGN-transfected 3T3 cells. Neutralization of DC/L-SIGN reduces ERK1/2 phosphorylation. DC/L-SIGN interactions with RSV G are not required for productive infection but are immunomodulatory, diminishing DC activation.","method":"Surface plasmon resonance, ERK phosphorylation assay in transfected cells, antibody neutralization, cytokine measurement","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR binding plus intracellular signaling with antibody controls, single lab","pmids":["22090124"],"is_preprint":false},{"year":2013,"finding":"CLEC4M binds and internalizes VWF; HEK 293 cells transfected with CLEC4M bound and internalized VWF (by immunofluorescence and ELISA). CLEC4M with 4 or 9 neck VNTR copies shows reduced interaction with VWF compared to CLEC4M with 7 VNTRs. In vivo, mice expressing CLEC4M after hydrodynamic liver transfer show 46% decrease in plasma VWF levels.","method":"CLEC4M-Fc pulldown, cell-based binding and internalization assays (immunofluorescence, ELISA), in vivo hydrodynamic liver transfer in mice","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, cell-based internalization, in vivo mouse model), replicated with different VNTR alleles","pmids":["23529928"],"is_preprint":false},{"year":2013,"finding":"Solution NMR analysis of the DC-SIGNR CRD reveals a different binding mode for Man9GlcNAc (derived from HIV gp120) compared to small glycan fragments; Man9GlcNAc induces ligand-induced conformational and dynamic changes distinct from those seen with Man3, Man5, or (GlcNAc)2Man3. The CRD is a highly flexible domain.","method":"Solution-state NMR spectroscopy, backbone assignment, 15N relaxation measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural and dynamic analysis with virus-derived ligand, single lab","pmids":["23788638"],"is_preprint":false},{"year":2013,"finding":"KSHV K5 ubiquitin ligase mediates down-regulation and degradation of DC-SIGNR after KSHV infection; K3 also targets DC-SIGNR in exogenous expression. Both K3 and K5 preferentially associate with immature (incompletely glycosylated) forms of DC-SIGNR and mediate their ubiquitylation. Multiple C-terminal trafficking motifs in K3/K5 are important for DC-SIGNR regulation.","method":"Pulldown assays, ubiquitylation assays, flow cytometry (surface expression), mutagenesis of trafficking motifs, viral infection experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown plus ubiquitylation with functional down-regulation assay, single lab","pmids":["23460925"],"is_preprint":false},{"year":2014,"finding":"NMR evidence demonstrates that the DC-SIGNR CRD reversibly releases glycan ligands at low pH (4.2 vs. 6.8), consistent with endocytic receptor behavior. Mannose-containing oligosaccharide binding is more strongly affected by pH than GlcNAc-containing oligosaccharide binding. Ca2+ binding is also reduced at low pH.","method":"Solution NMR pH titration experiments with multiple glycan ligands and calcium","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR with multiple glycans at multiple pH values, single lab","pmids":["24976257"],"is_preprint":false},{"year":2016,"finding":"L-SIGN acts as an attachment receptor (not an endocytic receptor) for phleboviruses (RVFV, TOSV, UUKV): an endocytosis-defective mutant of L-SIGN still mediates UUKV uptake and infection. This is mechanistically distinct from DC-SIGN, which acts as an authentic endocytic receptor for the same viruses.","method":"Infection assays with endocytosis-defective L-SIGN mutants, virus binding assays","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endocytosis-defective mutant analysis distinguishing attachment vs. endocytic function, single lab","pmids":["26990254"],"is_preprint":false},{"year":2016,"finding":"DC-SIGN and L-SIGN are authentic endocytic receptors for IAV entry: Lec2 sialic acid-deficient CHO cells expressing endocytosis-defective DC-SIGN/L-SIGN mutants retain virus-binding capacity but show reduced susceptibility to infection, confirming that endocytic function is required for productive IAV entry via these lectins.","method":"Infection assays in sialic acid-deficient Lec2 CHO cells expressing wild-type or endocytosis-defective DC-SIGN/L-SIGN mutants","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — endocytosis-defective mutant analysis in defined cell system, builds on prior work, single lab","pmids":["26763587"],"is_preprint":false},{"year":2016,"finding":"The neck domains of DC-SIGNR form more stable tetramers than DC-SIGN due to two structural features: a leucine in the first position of the hydrophobic heptad pattern and an arginine forming an intra-chain salt bridge with glutamic acid. In DC-SIGNR, stable repeat units predominate throughout the neck, holding CRDs relatively close together, whereas in DC-SIGN, destabilizing residues near the CRDs allow them to splay further apart.","method":"Gel filtration, differential scanning calorimetry, circular dichroism of model polypeptides with uniform repeat units","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic biophysical analysis of designed constructs, multiple methods, single lab","pmids":["27859859"],"is_preprint":false},{"year":2019,"finding":"CLEC4M is an endocytic clearance receptor for factor VIII (FVIII): CLEC4M-expressing HEK 293 cells bind and internalize both recombinant and plasma-derived FVIII through VWF-dependent and VWF-independent mechanisms. CLEC4M binding to FVIII requires mannose-exposed N-linked glycans. FVIII internalization via CLEC4M proceeds through a clathrin-coated pit-dependent mechanism, routing FVIII through early and late endosomes to lysosomes. In vivo hepatic CLEC4M expression in mice decreases plasma FVIII:C levels.","method":"Cell-based binding and internalization assays, solid-phase binding assay, in vivo hydrodynamic liver transfer, immunohistochemistry, pharmacological inhibition of clathrin-dependent endocytosis","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, defined mechanism (clathrin-coated pits, endosomal trafficking), single lab","pmids":["30740857"],"is_preprint":false},{"year":2021,"finding":"CD209L/L-SIGN (CLEC4M) acts as a receptor for SARS-CoV-2: it binds the SARS-CoV-2 spike receptor-binding domain (S-RBD), and knockdown of CD209L or treatment with soluble CD209L inhibits SARS-CoV-2 entry into human endothelial cells. CD209L also interacts with ACE2, suggesting heterodimerization in cells where both are expressed. Removal of N-glycosylation at site N92 of CD209L enhances S-RBD binding.","method":"Multiple biochemical binding assays (ELISA, co-immunoprecipitation), siRNA knockdown, pseudovirus and authentic virus infection assays, N-glycosylation mutagenesis, immunofluorescence","journal":"ACS central science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods, knockdown with functional readout, glycosylation mutagenesis, confirmed with authentic virus","pmids":["34341769"],"is_preprint":false},{"year":2021,"finding":"L-SIGN interacts in a Ca2+-dependent manner with high-mannose-type N-glycans on the SARS-CoV-2 spike protein and is highly expressed on human liver sinusoidal endothelial cells (LSECs) and lymph node lymphatic endothelial cells. Both pseudotyped and authentic SARS-CoV-2 infect L-SIGN-expressing cells, and blocking L-SIGN function reduces infection. SARS-CoV-2 infection of LSECs (demonstrated by viral proteins in liver autopsy) was associated with elevated vWF and FVIII expression.","method":"High-resolution confocal microscopy of liver autopsy samples, pseudovirus and authentic virus infection assays, L-SIGN blocking experiments, immunofluorescence","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional infection assays with blocking, histological evidence in human tissue, authentic virus used","pmids":["34291736"],"is_preprint":false},{"year":2021,"finding":"DC-SIGN and L-SIGN bind to diverse glycans on the SARS-CoV-2 spike protein at multiple interaction areas and promote SARS-CoV-2 trans-infection to ACE2+ cells; a glycomimetic antagonist designed against DC-SIGN inhibits this process. This was confirmed with authentic SARS-CoV-2 virus.","method":"Pseudovirus and authentic SARS-CoV-2 trans-infection assays, glycomimetic inhibitor competition, human respiratory cell lines","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional trans-infection assay with authentic virus and specific inhibitor, multiple cell types","pmids":["34015061"],"is_preprint":false},{"year":2024,"finding":"Man84 (a mannose derivative with a methylene guanidine triazole at position 2) is the first selective L-SIGN ligand, binding L-SIGN with KD ~12.7 μM with 50-fold selectivity over DC-SIGN. X-ray structure of the L-SIGN CRD/Man84 complex reveals that selectivity derives from a single amino acid difference between the two CRDs, where the guanidinium group achieves steric and electrostatic complementarity with L-SIGN. Dimeric Man84 achieves nanomolar avidity and selectively inhibits L-SIGN-dependent trans-infection by SARS-CoV-2 and Ebola virus.","method":"X-ray crystallography of CRD/ligand complex, ITC binding measurements, SPR, NMR conformational analysis, pseudovirus trans-infection inhibition assay","journal":"Chemical science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by ITC, SPR, NMR, and trans-infection assay; identifies single residue basis of selectivity","pmids":["39246372"],"is_preprint":false}],"current_model":"CLEC4M (L-SIGN/DC-SIGNR/CD299) is a type II transmembrane C-type lectin that forms tetramers through an alpha-helical neck domain, projects four calcium-dependent carbohydrate recognition domains (CRDs) that selectively bind high-mannose N-glycans on pathogens and endogenous glycoproteins, and functions primarily as an adhesion/attachment receptor on liver sinusoidal and lymph node endothelial cells—capturing viruses (HIV, SARS-CoV, SARS-CoV-2, Ebola, HCV, WNV, influenza) and trans-infecting adjacent susceptible cells via endocytosis; it additionally serves as a clearance receptor for VWF and FVIII through a clathrin-dependent, mannose-glycan-mediated internalization pathway, with its neck-repeat polymorphisms modulating tetramer stability, ligand-binding affinity, and consequently plasma VWF/FVIII levels and susceptibility to infection."},"narrative":{"mechanistic_narrative":"CLEC4M (L-SIGN/DC-SIGNR) is a type II transmembrane C-type lectin that functions as a calcium-dependent, high-mannose-glycan recognition receptor on liver sinusoidal, lymph node, and placental endothelial cells, where it captures glycosylated pathogens and clears endogenous glycoproteins [PMID:11739956, PMID:11226297]. Its extracellular region forms a tetramer stabilized by an alpha-helical neck of segmented four-helix bundles that holds four flexibly linked carbohydrate-recognition domains (CRDs) in a clustered arrangement, enabling high-avidity multivalent binding to Man9GlcNAc2 N-glycans [PMID:11384997, PMID:15509576, PMID:19835887, PMID:27859859]; CLEC4M neck tetramers are intrinsically more stable than those of its paralog DC-SIGN owing to defined heptad and salt-bridge residues [PMID:27859859]. Through this glycan-recognition activity CLEC4M serves as an attachment and/or entry receptor for a broad range of viruses — HIV/SIV, HCV, SARS-CoV, West Nile virus, Ebola, influenza A, RSV, and SARS-CoV-2 — binding high-mannose N-glycans on viral envelope glycoproteins and trans-infecting adjacent susceptible cells [PMID:11226297, PMID:15371595, PMID:15496474, PMID:16415006, PMID:18083206, PMID:21191006, PMID:34341769, PMID:34015061]. Its functional behavior is virus-dependent: it acts purely as a non-endocytic attachment receptor for phleboviruses yet requires endocytic function for productive influenza A entry [PMID:26990254, PMID:26763587]. CLEC4M also operates as a physiological clearance receptor, binding and internalizing von Willebrand factor and factor VIII via mannose-exposed N-glycans through clathrin-coated pits that route ligand through endosomes to lysosomes, thereby lowering plasma VWF and FVIII levels in vivo [PMID:23529928, PMID:30740857]. Polymorphic neck-repeat (VNTR) variation tunes tetramer stability and ligand affinity, modulating both viral susceptibility and VWF/FVIII binding [PMID:16369534, PMID:16621794, PMID:23529928], and the single CRD residue distinguishing CLEC4M from DC-SIGN (Ser363 vs Val351) dictates fucose/Lewis-antigen and ligand-binding selectivity that has been exploited to design selective small-molecule antagonists [PMID:15184372, PMID:39246372].","teleology":[{"year":2001,"claim":"Established the structural and biochemical basis of ligand recognition — that CLEC4M selectively binds high-mannose N-glycans via calcium-dependent CRDs and uses an alpha-helical neck to oligomerize for multivalent, high-avidity binding.","evidence":"X-ray crystallography of CRD-oligosaccharide complexes, cross-linking, ultracentrifugation, CD, and binding assays with recombinant fragments","pmids":["11739956","11384997"],"confidence":"High","gaps":["Did not address receptor behavior in the context of full-length receptor on cells","Endogenous physiological ligands not yet defined"]},{"year":2001,"claim":"Defined a biological role by showing CLEC4M captures HIV/SIV and trans-infects T cells in a carbohydrate-dependent manner, and localized it to sinusoidal and lymphatic endothelium.","evidence":"Cell-based trans-infection assays with carbohydrate competition and tissue immunostaining","pmids":["11226297"],"confidence":"High","gaps":["Mechanism distinguishing capture from productive entry not resolved","Did not establish whether CLEC4M endocytoses or merely tethers virus"]},{"year":2004,"claim":"Distinguished CLEC4M from its paralog DC-SIGN functionally and molecularly: CLEC4M does not release ligand at endosomal pH or mediate endocytosis under these conditions and has a restricted glycan specificity set by a single CRD residue (Ser363 vs DC-SIGN Val351).","evidence":"Glycan array screening, site-directed mutagenesis, structural analysis, pH-dependent release and endocytosis assays","pmids":["15195147","15184372"],"confidence":"High","gaps":["The non-endocytic conclusion was later shown to be virus-context dependent","Did not map full repertoire of physiological glycoprotein ligands"]},{"year":2004,"claim":"Broadened the receptor's pathogen range, identifying CLEC4M as an entry receptor for SARS-CoV and as a high-mannose-dependent capture/transinfection receptor for HCV.","evidence":"cDNA rescue in non-permissive CHO cells, pseudovirus infection, co-culture transinfection, and inhibitor (mannan/EGTA/antibody) controls","pmids":["15496474","15371595","15254204"],"confidence":"High","gaps":["Relative contribution of CLEC4M versus other receptors in vivo not quantified","Trafficking route of internalized virus only partially characterized"]},{"year":2004,"claim":"Resolved the architecture of the neck, establishing that N-terminal repeats stabilize the tetramer while the CRD-proximal portion supports dimerization, with CRDs flexibly linked.","evidence":"Cross-linking of full-length receptor in fibroblasts, hydrodynamic analysis, X-ray crystallography of truncated constructs, and DSC","pmids":["15509576","15784257"],"confidence":"High","gaps":["Did not connect neck length variation to in vivo function","Full-length extracellular domain structure not yet solved"]},{"year":2005,"claim":"Linked CLEC4M neck-repeat genotype to function and disease, showing homozygosity increases SARS-CoV binding and proteasomal degradation while reducing trans-infection, conferring protection.","evidence":"Genetic association combined with cell-based binding, viral degradation, and trans-infection assays on genotyped cells","pmids":["16369534"],"confidence":"High","gaps":["Causal mechanism connecting homozygosity to enhanced degradation not fully defined","Association not separated from linked loci"]},{"year":2006,"claim":"Clarified how polymorphic neck-repeat alleles affect function and oligomerization, showing most variants tetramerize and capture virus comparably and that only the shortest neck form is defective in homotetramer assembly.","evidence":"Viral infection enhancement, tetramerization and coexpression assays, cross-linking, analytical ultracentrifugation, affinity-tagging in transfected fibroblasts","pmids":["16413044","16621794"],"confidence":"High","gaps":["Physiological consequence of hetero-oligomer formation unresolved","Did not test endogenous ligand binding across alleles"]},{"year":2006,"claim":"Defined paralog-specific viral tropism, mapping CLEC4M's superior West Nile virus binding/infection to its CRD via chimera analysis.","evidence":"Chimeric receptor domain-swap, infection assays, and virus binding affinity measurements","pmids":["16415006"],"confidence":"High","gaps":["Specific CRD residues responsible not pinpointed","In vivo relevance to WNV pathogenesis untested"]},{"year":2007,"claim":"Established the molecular determinants on the viral side and a route of receptor regulation, identifying critical spike glycosylation sites for SARS-CoV entry and protease-mediated shedding of CLEC4M.","evidence":"Site-directed mutagenesis of spike glycosylation sites with infection assays; Der p 1 cleavage characterized by MS, N-terminal sequencing, and ICAM-3 binding","pmids":["17715238","17250696"],"confidence":"Medium","gaps":["Physiological/allergic relevance of CLEC4M shedding not established","ICAM-3 as an endogenous ligand only indirectly assessed"]},{"year":2009,"claim":"Refined understanding of neck assembly and CRD dynamics, showing the neck tetramerizes autonomously as segmented four-helix bundles and that CLEC4M tetramers are more stable than DC-SIGN's, and mapped the CRD-level basis for divergent HIV-1 transmission.","evidence":"Gel filtration, DSC, CD on isolated neck domains; crystallography of multi-repeat fragment; chimera and point-mutagenesis trans-infection assays","pmids":["19249311","19835887","19833723"],"confidence":"High","gaps":["Why CLEC4M fails to transmit HIV-1 despite binding gp120 not fully reconciled mechanistically","Single-residue rescue (K270W) insufficient, indicating additional determinants unidentified"]},{"year":2010,"claim":"Extended the receptor's role to sialic-acid-independent influenza A attachment and entry dependent on mannose-rich viral glycans and Ca2+-dependent lectin activity.","evidence":"Infection in sialic-acid-deficient Lec2 CHO cells with mannan competition, Ca2+ chelation, and neuraminidase controls","pmids":["21191006"],"confidence":"High","gaps":["Strain-dependence (H1N1 inefficiency) not mechanistically dissected","In vivo contribution to influenza tropism untested"]},{"year":2011,"claim":"Showed CLEC4M is signaling-competent and immunomodulatory, with RSV G protein binding triggering ERK1/2 phosphorylation independent of productive infection.","evidence":"Surface plasmon resonance, ERK phosphorylation in transfected cells, antibody neutralization, cytokine measurement","pmids":["22090124"],"confidence":"Medium","gaps":["Intracellular signaling intermediates linking CRD engagement to ERK not identified","Single cell-line system without primary DC validation"]},{"year":2013,"claim":"Identified the first endogenous clearance ligand, demonstrating CLEC4M binds and internalizes VWF in an allele-dependent manner and lowers plasma VWF in vivo.","evidence":"CLEC4M-Fc pulldown, cell-based binding/internalization (IF, ELISA), and in vivo hydrodynamic liver transfer in mice","pmids":["23529928"],"confidence":"High","gaps":["Internalization route and intracellular fate of VWF not detailed in this study","Did not establish receptor recycling versus degradation"]},{"year":2013,"claim":"Provided dynamic structural insight into ligand recognition and a virus-driven degradation pathway, showing Man9GlcNAc induces a distinct CRD binding mode/conformation and that KSHV K3/K5 ubiquitin ligases downregulate immature CLEC4M.","evidence":"Solution NMR with backbone assignment and 15N relaxation; pulldown, ubiquitylation, flow cytometry, and mutagenesis of trafficking motifs","pmids":["23788638","23460925"],"confidence":"Medium","gaps":["Functional consequence of CRD flexibility for avidity not quantified","K3/K5 downregulation shown largely in exogenous expression systems"]},{"year":2014,"claim":"Reconciled the endocytic-receptor question at the glycan level, demonstrating CLEC4M CRDs reversibly release mannose glycans and Ca2+ at low pH consistent with endocytic-receptor behavior.","evidence":"Solution NMR pH-titration with multiple glycan ligands and calcium","pmids":["24976257"],"confidence":"Medium","gaps":["pH-release of isolated CRD not directly linked to cellular endocytic flux","Reconciliation with earlier non-endocytic conclusions context-dependent"]},{"year":2016,"claim":"Resolved that CLEC4M's endocytic versus attachment role is pathogen-specific — non-endocytic for phleboviruses but endocytosis-dependent for productive influenza A entry.","evidence":"Infection assays with endocytosis-defective L-SIGN mutants in defined cell systems","pmids":["26990254","26763587"],"confidence":"High","gaps":["Molecular switch determining endocytic versus tethering outcome per virus unknown","Cytoplasmic-tail trafficking signals not mapped"]},{"year":2016,"claim":"Defined the structural code for the superior tetramer stability of CLEC4M relative to DC-SIGN, attributing it to a heptad leucine and an arginine–glutamate intra-chain salt bridge that cluster CRDs.","evidence":"Gel filtration, DSC, and CD of model polypeptides with uniform repeat units","pmids":["27859859"],"confidence":"High","gaps":["Effect of CRD clustering geometry on avidity for natural ligands not directly measured","Designed constructs rather than native receptor"]},{"year":2019,"claim":"Established CLEC4M as a bona fide endocytic clearance receptor for factor VIII, defining the clathrin-dependent route through endosomes to lysosomes and its in vivo effect on plasma FVIII.","evidence":"Cell-based binding/internalization, solid-phase binding, clathrin-inhibition pharmacology, in vivo hydrodynamic liver transfer, and IHC","pmids":["30740857"],"confidence":"High","gaps":["Relative contribution of VWF-dependent versus VWF-independent FVIII uptake in vivo not quantified","Receptor fate after ligand delivery to lysosome not tracked"]},{"year":2021,"claim":"Established CLEC4M as a SARS-CoV-2 receptor on endothelium, binding spike high-mannose glycans/RBD, mediating entry and trans-infection of ACE2+ cells, with potential ACE2 heterodimerization and links to elevated VWF/FVIII in infected liver.","evidence":"ELISA/Co-IP binding, siRNA knockdown, pseudovirus and authentic virus infection, glycosylation mutagenesis, confocal microscopy of liver autopsy, and glycomimetic inhibition","pmids":["34341769","34291736","34015061"],"confidence":"High","gaps":["In vivo role of CLEC4M-ACE2 heterodimerization in SARS-CoV-2 pathogenesis unresolved","Causal link between LSEC infection and elevated VWF/FVIII not mechanistically proven"]},{"year":2024,"claim":"Translated the single-residue CRD difference into a selective ligand, designing Man84 whose guanidinium achieves CLEC4M-selective complementarity and, as a dimer, inhibits CLEC4M-dependent trans-infection by SARS-CoV-2 and Ebola.","evidence":"X-ray crystallography of CRD/ligand complex, ITC, SPR, NMR, and pseudovirus trans-infection inhibition","pmids":["39246372"],"confidence":"High","gaps":["In vivo efficacy and pharmacokinetics of Man84 untested","Selectivity against other C-type lectins not broadly profiled"]},{"year":null,"claim":"The molecular switch that determines whether CLEC4M tethers a ligand at the surface versus internalizes it, and the in vivo balance of its antiviral capture versus VWF/FVIII clearance functions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined cytoplasmic-tail signal mapped that toggles endocytic versus attachment behavior","Endogenous ligand repertoire beyond VWF, FVIII, and ICAM-3 incompletely cataloged","No structure of the full-length tetrameric receptor engaging a multivalent natural ligand"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,4,6,11,20,30,31,32]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[22,29]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,23]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,5,15,31]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,29]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[29]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,9,30,31,32]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,27,29]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[22,29]}],"complexes":[],"partners":["VWF","F8","ACE2","ICAM3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2X3","full_name":"C-type lectin domain family 4 member M","aliases":["CD209 antigen-like protein 1","DC-SIGN-related protein","DC-SIGNR","Dendritic cell-specific ICAM-3-grabbing non-integrin 2","DC-SIGN2","Liver/lymph node-specific ICAM-3-grabbing non-integrin","L-SIGN"],"length_aa":399,"mass_kda":45.4,"function":"Probable pathogen-recognition receptor involved in peripheral immune surveillance in liver. May mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. Is a receptor for ICAM3, probably by binding to mannose-like carbohydrates (Microbial infection) Acts as an attachment receptor for Ebolavirus (Microbial infection) Acts as an attachment receptor for Hepatitis C virus (Microbial infection) Acts as an attachment receptor for HIV-1 (Microbial infection) Acts as an attachment receptor for Human coronavirus 229E (Microbial infection) Acts as an attachment receptor for Human cytomegalovirus/HHV-5 (Microbial infection) Acts as an attachment receptor for Influenzavirus (Microbial infection) Acts as an attachment receptor for SARS-CoV (Microbial infection) Acts as an attachment receptor for West-nile virus (Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus (Microbial infection) Acts as an attachment receptor for Marburg virus glycoprotein (Microbial infection) Recognition of M.bovis by dendritic cells may occur partially via this molecule","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9H2X3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLEC4M","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLEC4M","total_profiled":1310},"omim":[{"mim_id":"616256","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER G; CLEC4G","url":"https://www.omim.org/entry/616256"},{"mim_id":"605872","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER M; CLEC4M","url":"https://www.omim.org/entry/605872"},{"mim_id":"604672","title":"CD209 ANTIGEN; CD209","url":"https://www.omim.org/entry/604672"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":58.6},{"tissue":"lymphoid tissue","ntpm":15.4}],"url":"https://www.proteinatlas.org/search/CLEC4M"},"hgnc":{"alias_symbol":["L-SIGN","CD209L1","HP10347","DC-SIGNR","LSIGN","DCSIGNR","DC-SIGN2"],"prev_symbol":["CD209L","CD299"]},"alphafold":{"accession":"Q9H2X3","domains":[{"cath_id":"3.10.100.10","chopping":"274-393","consensus_level":"high","plddt":97.3051,"start":274,"end":393},{"cath_id":"1.20.1440","chopping":"130-219","consensus_level":"medium","plddt":56.9747,"start":130,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2X3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2X3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2X3-F1-predicted_aligned_error_v6.png","plddt_mean":70.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLEC4M","jax_strain_url":"https://www.jax.org/strain/search?query=CLEC4M"},"sequence":{"accession":"Q9H2X3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2X3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2X3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2X3"}},"corpus_meta":[{"pmid":"11739956","id":"PMC_11739956","title":"Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11739956","citation_count":553,"is_preprint":false},{"pmid":"12050398","id":"PMC_12050398","title":"C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12050398","citation_count":519,"is_preprint":false},{"pmid":"15195147","id":"PMC_15195147","title":"Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR.","date":"2004","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15195147","citation_count":477,"is_preprint":false},{"pmid":"15496474","id":"PMC_15496474","title":"CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15496474","citation_count":459,"is_preprint":false},{"pmid":"11384997","id":"PMC_11384997","title":"A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. 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CRD-oligosaccharide complexes combined with binding studies\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional binding validation, independently replicated by multiple subsequent structural studies\",\n      \"pmids\": [\"11739956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The extracellular domain of DC-SIGNR (and DC-SIGN) forms a tetramer stabilized by an alpha-helical stalk (neck region). The CRDs bind Man9GlcNAc2 oligosaccharide with 17-fold higher affinity than mannose alone, and affinity for a glycopeptide bearing two such oligosaccharides is increased a further 5- to 25-fold, demonstrating multivalent/oligomeric binding.\",\n      \"method\": \"Chemical cross-linking, equilibrium ultracentrifugation, circular dichroism, binding assays with recombinant fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with multiple orthogonal biophysical methods, replicated by subsequent structural studies\",\n      \"pmids\": [\"11384997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DC-SIGNR binds to multiple strains of HIV-1, HIV-2, and SIV and transmits these viruses to T cell lines and PBMCs in trans; binding is dependent on carbohydrate recognition. DC-SIGNR is expressed on sinusoidal endothelial cells in liver, lymph node sinuses, and placental villi.\",\n      \"method\": \"Cell-based trans-infection assay, carbohydrate competition, immunostaining\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional trans-infection assay with carbohydrate-dependence controls, replicated by multiple independent labs\",\n      \"pmids\": [\"11226297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Unlike DC-SIGN (which mediates endocytosis and releases ligand at endosomal pH as a recycling receptor), DC-SIGNR does not release ligand at low pH and does not mediate endocytosis, functioning only as an adhesion receptor with a restricted ligand-binding profile. DC-SIGN and DC-SIGNR also have distinct ligand-binding properties: only DC-SIGN binds blood group antigens including fucosylated structures; both bind high-mannose oligosaccharides. A single amino acid difference (Val351 in DC-SIGN vs. Ser363 in DC-SIGNR) in the CRD determines fucose-binding specificity.\",\n      \"method\": \"Glycan array screening, structural analysis, mutagenesis, pH-dependent ligand-release assays, endocytosis assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (glycan array, mutagenesis, structure, functional assays) in a single rigorous study\",\n      \"pmids\": [\"15195147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD209L/L-SIGN (CLEC4M) acts as an alternative receptor for SARS-CoV entry, mediating susceptibility to SARS-CoV infection in otherwise non-permissive CHO cells when the CD209L cDNA is transfected. L-SIGN is expressed in human lung type II alveolar cells and endothelial cells.\",\n      \"method\": \"cDNA library screen, retroviral pseudotype infection assay, RT-PCR for viral replication, transfection and infection of CHO cells, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct receptor identification by cDNA rescue in non-permissive cells, confirmed with authentic virus, replicated by independent labs\",\n      \"pmids\": [\"15496474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The extended neck region of DC-SIGNR stabilizes tetramers; regions near the N-terminus are needed for tetramer stability whereas the portion adjacent to the CRD is sufficient for dimer formation. Crystal structures of truncated DC-SIGNR show CRDs are flexibly linked to the neck, which has alpha-helical segments interspersed with non-helical regions. Cross-linking of full-length receptors in fibroblasts confirms the tetrameric state.\",\n      \"method\": \"Chemical cross-linking of full-length receptor in fibroblasts, hydrodynamic analysis, X-ray crystallography of truncated constructs, differential scanning calorimetry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with multiple biophysical methods and cell-based confirmation\",\n      \"pmids\": [\"15509576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"L-SIGN and DC-SIGN capture HCV by binding to HCV envelope glycoprotein E2 via high-mannose N-glycans (blocked by mannan, EGTA, and anti-CRD antibodies), and SIGN-HCV pseudovirus complexes are internalized and then transinfect adjacent human liver cells; virus capture and transinfection require internalization of the SIGN-HCV complex.\",\n      \"method\": \"HCV pseudovirus entry assay, co-culture transinfection assay, inhibitor studies (mannan, EGTA, antibodies)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional trans-infection assay with multiple inhibitor controls, replicated across multiple labs\",\n      \"pmids\": [\"15371595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The molecular basis for DC-SIGN vs. L-SIGN difference in Lewis antigen binding is a single amino acid: Val351 in DC-SIGN creates a hydrophobic pocket for Fucα1,3/4-GlcNAc interaction, while the equivalent Ser363 in L-SIGN creates a hydrophilic pocket preventing Lex (Fucα1,3-GlcNAc) but supporting Lea/Leb binding. The S363V gain-of-function L-SIGN mutant acquired Lex binding.\",\n      \"method\": \"Binding assays with neoglycoconjugates, site-directed mutagenesis, molecular modeling and docking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional binding assays and structural modeling in single study\",\n      \"pmids\": [\"15184372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"L-SIGN (expressed by THP-1 cells) internalizes HCV particles into non-lysosomal compartments, protecting them from lysosomal degradation, in a manner similar to DC-SIGN. This suggests L-SIGN on liver sinusoidal endothelial cells captures HCV from blood and transmits it to hepatocytes.\",\n      \"method\": \"Cell-based internalization assays, confocal microscopy of intracellular HCV trafficking, antibody blocking\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of internalization route, single lab, two complementary methods\",\n      \"pmids\": [\"15254204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Homozygous L-SIGN (CLEC4M) cells show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and lower capacity for trans-infection compared to heterozygous cells, demonstrating that CLEC4M neck-repeat homozygosity confers a protective role during SARS infection.\",\n      \"method\": \"Genetic association study combined with cell-based binding assays, viral degradation assays, and trans-infection assays on homozygous vs. heterozygous cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional cell-based assays linked to genotype, multiple mechanistic readouts\",\n      \"pmids\": [\"16369534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The crystal structure of DC-SIGNR with its last repeat region reveals conformational changes in calcium/carbohydrate coordination loops of the CRD, an additional disulfide bond between N and C termini of the CRD, and a helical conformation for the last repeat, enabling generation of a tetramer model for DC-SIGN/R.\",\n      \"method\": \"X-ray crystallography, homology modeling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with detailed structural analysis, single lab\",\n      \"pmids\": [\"15784257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGNR promotes West Nile virus (WNV) infection much more efficiently than DC-SIGN; this differential utilization maps to the carbohydrate recognition domain of DC-SIGNR via chimera analysis, and WNV virions bind DC-SIGNR with much greater affinity than DC-SIGN.\",\n      \"method\": \"Chimeric receptor analysis, infection assays in transfected cells, virus binding affinity measurements\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimera domain-swap experiments with quantitative binding and infection assays, single lab\",\n      \"pmids\": [\"16415006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGNR neck-domain polymorphic alleles with five and six repeat units bind viral glycoproteins, augment viral infection, and tetramerize with comparable efficiency to the wild-type seven-repeat allele. Coexpression of wt and five-repeat alleles does not decrease pathogen capture, indicating potential hetero-oligomers do not impair function.\",\n      \"method\": \"Viral infection enhancement assays, tetramerization assays, coexpression experiments\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts, single lab\",\n      \"pmids\": [\"16413044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Only the smallest (shortest neck) polymorphic form of DC-SIGNR is defective in homotetramer assembly, whereas DC-SIGNR polypeptides of different neck lengths form stable heterotetramers detectable in transfected fibroblasts.\",\n      \"method\": \"Chemical cross-linking, analytical ultracentrifugation, affinity-tagging approach, transfected fibroblast expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods plus cell-based confirmation, single lab\",\n      \"pmids\": [\"16621794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Seven specific asparagine-linked glycosylation sites on the SARS-CoV spike protein (N109, N118, N119, N158, N227, N589, N699) are critical for DC/L-SIGN-mediated virus entry; these sites are distinct from the ACE2-binding domain, and both DC-SIGN and L-SIGN can function as independent entry receptors for SARS-CoV.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation sites on spike protein, pseudovirus infection assays in DC/L-SIGN-expressing cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic site-directed mutagenesis combined with functional infection assays, single lab\",\n      \"pmids\": [\"17715238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Der p 1 cysteine protease cleaves DC-SIGNR from the cell surface at a major cleavage site; loss of DC-SIGNR from the cell surface reduces binding of the endogenous ligand ICAM-3.\",\n      \"method\": \"In silico substrate prediction (PoPS), cell-surface cleavage assays, purified recombinant protein digestion, N-terminal sequencing, MALDI mass spectrometry, ICAM-3 binding assay\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteolytic cleavage identified by MS and sequencing with functional consequence shown, single lab\",\n      \"pmids\": [\"17250696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DC-SIGNR (co-expressed with LSECtin on liver, lymph node, and bone marrow sinusoidal endothelial cells) binds soluble Ebola virus glycoprotein with affinity comparable to LSECtin. Unlike DC-SIGN, DC-SIGNR does not efficiently capture HIV-1 particles (despite binding soluble HIV-1 GP), and exposure to low-pH releases ligand from DC-SIGNR (but not from LSECtin).\",\n      \"method\": \"Binding affinity measurements, virion capture assays, pH-dependent ligand release assays, co-expression immunostaining\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays, single lab\",\n      \"pmids\": [\"18083206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Neck domains of DC-SIGNR expressed in isolation form tetramers autonomously without the CRDs, and stability of tetramers depends on neck domain sequences. Neck and CRD domains are organized independently. Polymorphic DC-SIGNR forms with fewer repeats show modestly reduced stability; DC-SIGNR tetramers are significantly more stable than DC-SIGN tetramers.\",\n      \"method\": \"Gel filtration, differential scanning calorimetry, circular dichroism, isolated neck domain expression\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods on isolated domain, single lab\",\n      \"pmids\": [\"19249311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The neck region of DC-SIGNR forms a segmented helical structure consisting of four-helix bundles connected by short non-helical linkers, as determined by crystallography of a multi-repeat fragment. The CRDs are flexibly linked to the neck. An almost-complete model of the DC-SIGNR extracellular domain was derived.\",\n      \"method\": \"X-ray crystallography of multi-repeat neck fragment\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of multi-repeat domain, single lab\",\n      \"pmids\": [\"19835887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DC-SIGN transmits HIV-1 to target cells while L-SIGN does not, due to differences in the carbohydrate recognition domain (CRD). Replacement of the DC-SIGN CRD with that of L-SIGN abolishes virus binding and transmission; conversely, the DC-SIGN CRD confers HIV-1 binding/transmission to L-SIGN chimeras. Trp-258 in the DC-SIGN CRD is essential for HIV-1 transmission, and K270W mutation alone in L-SIGN is insufficient.\",\n      \"method\": \"DC-SIGN/L-SIGN chimera analysis in Raji B cells, site-directed mutagenesis, trans-infection assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-swap chimeras plus point mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"19833723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DC-SIGN and L-SIGN can mediate sialic acid-independent attachment and entry of influenza A viruses (H3N2) in sialic acid-deficient Lec2 CHO cells, dependent on mannose-rich N-linked glycans on the virus and Ca2+-dependent lectin activity. H1N1 strains with low mannose-rich glycans are inefficient at infecting DC-SIGN/L-SIGN-expressing cells.\",\n      \"method\": \"Infection assay in sialic-acid-deficient CHO cells expressing DC-SIGN or L-SIGN, mannan competition, Ca2+ chelation, bacterial neuraminidase controls\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — definitive receptor assay using SA-deficient cells with multiple controls, single lab\",\n      \"pmids\": [\"21191006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RSV attachment glycoprotein G binds both DC-SIGN and L-SIGN (measured by surface plasmon resonance), and this interaction triggers ERK1 and ERK2 phosphorylation in DC/L-SIGN-transfected 3T3 cells. Neutralization of DC/L-SIGN reduces ERK1/2 phosphorylation. DC/L-SIGN interactions with RSV G are not required for productive infection but are immunomodulatory, diminishing DC activation.\",\n      \"method\": \"Surface plasmon resonance, ERK phosphorylation assay in transfected cells, antibody neutralization, cytokine measurement\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR binding plus intracellular signaling with antibody controls, single lab\",\n      \"pmids\": [\"22090124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLEC4M binds and internalizes VWF; HEK 293 cells transfected with CLEC4M bound and internalized VWF (by immunofluorescence and ELISA). CLEC4M with 4 or 9 neck VNTR copies shows reduced interaction with VWF compared to CLEC4M with 7 VNTRs. In vivo, mice expressing CLEC4M after hydrodynamic liver transfer show 46% decrease in plasma VWF levels.\",\n      \"method\": \"CLEC4M-Fc pulldown, cell-based binding and internalization assays (immunofluorescence, ELISA), in vivo hydrodynamic liver transfer in mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, cell-based internalization, in vivo mouse model), replicated with different VNTR alleles\",\n      \"pmids\": [\"23529928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Solution NMR analysis of the DC-SIGNR CRD reveals a different binding mode for Man9GlcNAc (derived from HIV gp120) compared to small glycan fragments; Man9GlcNAc induces ligand-induced conformational and dynamic changes distinct from those seen with Man3, Man5, or (GlcNAc)2Man3. The CRD is a highly flexible domain.\",\n      \"method\": \"Solution-state NMR spectroscopy, backbone assignment, 15N relaxation measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural and dynamic analysis with virus-derived ligand, single lab\",\n      \"pmids\": [\"23788638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KSHV K5 ubiquitin ligase mediates down-regulation and degradation of DC-SIGNR after KSHV infection; K3 also targets DC-SIGNR in exogenous expression. Both K3 and K5 preferentially associate with immature (incompletely glycosylated) forms of DC-SIGNR and mediate their ubiquitylation. Multiple C-terminal trafficking motifs in K3/K5 are important for DC-SIGNR regulation.\",\n      \"method\": \"Pulldown assays, ubiquitylation assays, flow cytometry (surface expression), mutagenesis of trafficking motifs, viral infection experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown plus ubiquitylation with functional down-regulation assay, single lab\",\n      \"pmids\": [\"23460925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR evidence demonstrates that the DC-SIGNR CRD reversibly releases glycan ligands at low pH (4.2 vs. 6.8), consistent with endocytic receptor behavior. Mannose-containing oligosaccharide binding is more strongly affected by pH than GlcNAc-containing oligosaccharide binding. Ca2+ binding is also reduced at low pH.\",\n      \"method\": \"Solution NMR pH titration experiments with multiple glycan ligands and calcium\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with multiple glycans at multiple pH values, single lab\",\n      \"pmids\": [\"24976257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"L-SIGN acts as an attachment receptor (not an endocytic receptor) for phleboviruses (RVFV, TOSV, UUKV): an endocytosis-defective mutant of L-SIGN still mediates UUKV uptake and infection. This is mechanistically distinct from DC-SIGN, which acts as an authentic endocytic receptor for the same viruses.\",\n      \"method\": \"Infection assays with endocytosis-defective L-SIGN mutants, virus binding assays\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endocytosis-defective mutant analysis distinguishing attachment vs. endocytic function, single lab\",\n      \"pmids\": [\"26990254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DC-SIGN and L-SIGN are authentic endocytic receptors for IAV entry: Lec2 sialic acid-deficient CHO cells expressing endocytosis-defective DC-SIGN/L-SIGN mutants retain virus-binding capacity but show reduced susceptibility to infection, confirming that endocytic function is required for productive IAV entry via these lectins.\",\n      \"method\": \"Infection assays in sialic acid-deficient Lec2 CHO cells expressing wild-type or endocytosis-defective DC-SIGN/L-SIGN mutants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endocytosis-defective mutant analysis in defined cell system, builds on prior work, single lab\",\n      \"pmids\": [\"26763587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The neck domains of DC-SIGNR form more stable tetramers than DC-SIGN due to two structural features: a leucine in the first position of the hydrophobic heptad pattern and an arginine forming an intra-chain salt bridge with glutamic acid. In DC-SIGNR, stable repeat units predominate throughout the neck, holding CRDs relatively close together, whereas in DC-SIGN, destabilizing residues near the CRDs allow them to splay further apart.\",\n      \"method\": \"Gel filtration, differential scanning calorimetry, circular dichroism of model polypeptides with uniform repeat units\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic biophysical analysis of designed constructs, multiple methods, single lab\",\n      \"pmids\": [\"27859859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLEC4M is an endocytic clearance receptor for factor VIII (FVIII): CLEC4M-expressing HEK 293 cells bind and internalize both recombinant and plasma-derived FVIII through VWF-dependent and VWF-independent mechanisms. CLEC4M binding to FVIII requires mannose-exposed N-linked glycans. FVIII internalization via CLEC4M proceeds through a clathrin-coated pit-dependent mechanism, routing FVIII through early and late endosomes to lysosomes. In vivo hepatic CLEC4M expression in mice decreases plasma FVIII:C levels.\",\n      \"method\": \"Cell-based binding and internalization assays, solid-phase binding assay, in vivo hydrodynamic liver transfer, immunohistochemistry, pharmacological inhibition of clathrin-dependent endocytosis\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, defined mechanism (clathrin-coated pits, endosomal trafficking), single lab\",\n      \"pmids\": [\"30740857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD209L/L-SIGN (CLEC4M) acts as a receptor for SARS-CoV-2: it binds the SARS-CoV-2 spike receptor-binding domain (S-RBD), and knockdown of CD209L or treatment with soluble CD209L inhibits SARS-CoV-2 entry into human endothelial cells. CD209L also interacts with ACE2, suggesting heterodimerization in cells where both are expressed. Removal of N-glycosylation at site N92 of CD209L enhances S-RBD binding.\",\n      \"method\": \"Multiple biochemical binding assays (ELISA, co-immunoprecipitation), siRNA knockdown, pseudovirus and authentic virus infection assays, N-glycosylation mutagenesis, immunofluorescence\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods, knockdown with functional readout, glycosylation mutagenesis, confirmed with authentic virus\",\n      \"pmids\": [\"34341769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"L-SIGN interacts in a Ca2+-dependent manner with high-mannose-type N-glycans on the SARS-CoV-2 spike protein and is highly expressed on human liver sinusoidal endothelial cells (LSECs) and lymph node lymphatic endothelial cells. Both pseudotyped and authentic SARS-CoV-2 infect L-SIGN-expressing cells, and blocking L-SIGN function reduces infection. SARS-CoV-2 infection of LSECs (demonstrated by viral proteins in liver autopsy) was associated with elevated vWF and FVIII expression.\",\n      \"method\": \"High-resolution confocal microscopy of liver autopsy samples, pseudovirus and authentic virus infection assays, L-SIGN blocking experiments, immunofluorescence\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional infection assays with blocking, histological evidence in human tissue, authentic virus used\",\n      \"pmids\": [\"34291736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DC-SIGN and L-SIGN bind to diverse glycans on the SARS-CoV-2 spike protein at multiple interaction areas and promote SARS-CoV-2 trans-infection to ACE2+ cells; a glycomimetic antagonist designed against DC-SIGN inhibits this process. This was confirmed with authentic SARS-CoV-2 virus.\",\n      \"method\": \"Pseudovirus and authentic SARS-CoV-2 trans-infection assays, glycomimetic inhibitor competition, human respiratory cell lines\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional trans-infection assay with authentic virus and specific inhibitor, multiple cell types\",\n      \"pmids\": [\"34015061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Man84 (a mannose derivative with a methylene guanidine triazole at position 2) is the first selective L-SIGN ligand, binding L-SIGN with KD ~12.7 μM with 50-fold selectivity over DC-SIGN. X-ray structure of the L-SIGN CRD/Man84 complex reveals that selectivity derives from a single amino acid difference between the two CRDs, where the guanidinium group achieves steric and electrostatic complementarity with L-SIGN. Dimeric Man84 achieves nanomolar avidity and selectively inhibits L-SIGN-dependent trans-infection by SARS-CoV-2 and Ebola virus.\",\n      \"method\": \"X-ray crystallography of CRD/ligand complex, ITC binding measurements, SPR, NMR conformational analysis, pseudovirus trans-infection inhibition assay\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by ITC, SPR, NMR, and trans-infection assay; identifies single residue basis of selectivity\",\n      \"pmids\": [\"39246372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLEC4M (L-SIGN/DC-SIGNR/CD299) is a type II transmembrane C-type lectin that forms tetramers through an alpha-helical neck domain, projects four calcium-dependent carbohydrate recognition domains (CRDs) that selectively bind high-mannose N-glycans on pathogens and endogenous glycoproteins, and functions primarily as an adhesion/attachment receptor on liver sinusoidal and lymph node endothelial cells—capturing viruses (HIV, SARS-CoV, SARS-CoV-2, Ebola, HCV, WNV, influenza) and trans-infecting adjacent susceptible cells via endocytosis; it additionally serves as a clearance receptor for VWF and FVIII through a clathrin-dependent, mannose-glycan-mediated internalization pathway, with its neck-repeat polymorphisms modulating tetramer stability, ligand-binding affinity, and consequently plasma VWF/FVIII levels and susceptibility to infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLEC4M (L-SIGN/DC-SIGNR) is a type II transmembrane C-type lectin that functions as a calcium-dependent, high-mannose-glycan recognition receptor on liver sinusoidal, lymph node, and placental endothelial cells, where it captures glycosylated pathogens and clears endogenous glycoproteins [#0, #2]. Its extracellular region forms a tetramer stabilized by an alpha-helical neck of segmented four-helix bundles that holds four flexibly linked carbohydrate-recognition domains (CRDs) in a clustered arrangement, enabling high-avidity multivalent binding to Man9GlcNAc2 N-glycans [#1, #5, #18, #28]; CLEC4M neck tetramers are intrinsically more stable than those of its paralog DC-SIGN owing to defined heptad and salt-bridge residues [#28]. Through this glycan-recognition activity CLEC4M serves as an attachment and/or entry receptor for a broad range of viruses — HIV/SIV, HCV, SARS-CoV, West Nile virus, Ebola, influenza A, RSV, and SARS-CoV-2 — binding high-mannose N-glycans on viral envelope glycoproteins and trans-infecting adjacent susceptible cells [#2, #6, #4, #11, #16, #20, #30, #32]. Its functional behavior is virus-dependent: it acts purely as a non-endocytic attachment receptor for phleboviruses yet requires endocytic function for productive influenza A entry [#26, #27]. CLEC4M also operates as a physiological clearance receptor, binding and internalizing von Willebrand factor and factor VIII via mannose-exposed N-glycans through clathrin-coated pits that route ligand through endosomes to lysosomes, thereby lowering plasma VWF and FVIII levels in vivo [#22, #29]. Polymorphic neck-repeat (VNTR) variation tunes tetramer stability and ligand affinity, modulating both viral susceptibility and VWF/FVIII binding [#9, #13, #22], and the single CRD residue distinguishing CLEC4M from DC-SIGN (Ser363 vs Val351) dictates fucose/Lewis-antigen and ligand-binding selectivity that has been exploited to design selective small-molecule antagonists [#7, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the structural and biochemical basis of ligand recognition — that CLEC4M selectively binds high-mannose N-glycans via calcium-dependent CRDs and uses an alpha-helical neck to oligomerize for multivalent, high-avidity binding.\",\n      \"evidence\": \"X-ray crystallography of CRD-oligosaccharide complexes, cross-linking, ultracentrifugation, CD, and binding assays with recombinant fragments\",\n      \"pmids\": [\"11739956\", \"11384997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address receptor behavior in the context of full-length receptor on cells\", \"Endogenous physiological ligands not yet defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a biological role by showing CLEC4M captures HIV/SIV and trans-infects T cells in a carbohydrate-dependent manner, and localized it to sinusoidal and lymphatic endothelium.\",\n      \"evidence\": \"Cell-based trans-infection assays with carbohydrate competition and tissue immunostaining\",\n      \"pmids\": [\"11226297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing capture from productive entry not resolved\", \"Did not establish whether CLEC4M endocytoses or merely tethers virus\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Distinguished CLEC4M from its paralog DC-SIGN functionally and molecularly: CLEC4M does not release ligand at endosomal pH or mediate endocytosis under these conditions and has a restricted glycan specificity set by a single CRD residue (Ser363 vs DC-SIGN Val351).\",\n      \"evidence\": \"Glycan array screening, site-directed mutagenesis, structural analysis, pH-dependent release and endocytosis assays\",\n      \"pmids\": [\"15195147\", \"15184372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The non-endocytic conclusion was later shown to be virus-context dependent\", \"Did not map full repertoire of physiological glycoprotein ligands\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened the receptor's pathogen range, identifying CLEC4M as an entry receptor for SARS-CoV and as a high-mannose-dependent capture/transinfection receptor for HCV.\",\n      \"evidence\": \"cDNA rescue in non-permissive CHO cells, pseudovirus infection, co-culture transinfection, and inhibitor (mannan/EGTA/antibody) controls\",\n      \"pmids\": [\"15496474\", \"15371595\", \"15254204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of CLEC4M versus other receptors in vivo not quantified\", \"Trafficking route of internalized virus only partially characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the architecture of the neck, establishing that N-terminal repeats stabilize the tetramer while the CRD-proximal portion supports dimerization, with CRDs flexibly linked.\",\n      \"evidence\": \"Cross-linking of full-length receptor in fibroblasts, hydrodynamic analysis, X-ray crystallography of truncated constructs, and DSC\",\n      \"pmids\": [\"15509576\", \"15784257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect neck length variation to in vivo function\", \"Full-length extracellular domain structure not yet solved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked CLEC4M neck-repeat genotype to function and disease, showing homozygosity increases SARS-CoV binding and proteasomal degradation while reducing trans-infection, conferring protection.\",\n      \"evidence\": \"Genetic association combined with cell-based binding, viral degradation, and trans-infection assays on genotyped cells\",\n      \"pmids\": [\"16369534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal mechanism connecting homozygosity to enhanced degradation not fully defined\", \"Association not separated from linked loci\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Clarified how polymorphic neck-repeat alleles affect function and oligomerization, showing most variants tetramerize and capture virus comparably and that only the shortest neck form is defective in homotetramer assembly.\",\n      \"evidence\": \"Viral infection enhancement, tetramerization and coexpression assays, cross-linking, analytical ultracentrifugation, affinity-tagging in transfected fibroblasts\",\n      \"pmids\": [\"16413044\", \"16621794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of hetero-oligomer formation unresolved\", \"Did not test endogenous ligand binding across alleles\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined paralog-specific viral tropism, mapping CLEC4M's superior West Nile virus binding/infection to its CRD via chimera analysis.\",\n      \"evidence\": \"Chimeric receptor domain-swap, infection assays, and virus binding affinity measurements\",\n      \"pmids\": [\"16415006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific CRD residues responsible not pinpointed\", \"In vivo relevance to WNV pathogenesis untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the molecular determinants on the viral side and a route of receptor regulation, identifying critical spike glycosylation sites for SARS-CoV entry and protease-mediated shedding of CLEC4M.\",\n      \"evidence\": \"Site-directed mutagenesis of spike glycosylation sites with infection assays; Der p 1 cleavage characterized by MS, N-terminal sequencing, and ICAM-3 binding\",\n      \"pmids\": [\"17715238\", \"17250696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological/allergic relevance of CLEC4M shedding not established\", \"ICAM-3 as an endogenous ligand only indirectly assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Refined understanding of neck assembly and CRD dynamics, showing the neck tetramerizes autonomously as segmented four-helix bundles and that CLEC4M tetramers are more stable than DC-SIGN's, and mapped the CRD-level basis for divergent HIV-1 transmission.\",\n      \"evidence\": \"Gel filtration, DSC, CD on isolated neck domains; crystallography of multi-repeat fragment; chimera and point-mutagenesis trans-infection assays\",\n      \"pmids\": [\"19249311\", \"19835887\", \"19833723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why CLEC4M fails to transmit HIV-1 despite binding gp120 not fully reconciled mechanistically\", \"Single-residue rescue (K270W) insufficient, indicating additional determinants unidentified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the receptor's role to sialic-acid-independent influenza A attachment and entry dependent on mannose-rich viral glycans and Ca2+-dependent lectin activity.\",\n      \"evidence\": \"Infection in sialic-acid-deficient Lec2 CHO cells with mannan competition, Ca2+ chelation, and neuraminidase controls\",\n      \"pmids\": [\"21191006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Strain-dependence (H1N1 inefficiency) not mechanistically dissected\", \"In vivo contribution to influenza tropism untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CLEC4M is signaling-competent and immunomodulatory, with RSV G protein binding triggering ERK1/2 phosphorylation independent of productive infection.\",\n      \"evidence\": \"Surface plasmon resonance, ERK phosphorylation in transfected cells, antibody neutralization, cytokine measurement\",\n      \"pmids\": [\"22090124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling intermediates linking CRD engagement to ERK not identified\", \"Single cell-line system without primary DC validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the first endogenous clearance ligand, demonstrating CLEC4M binds and internalizes VWF in an allele-dependent manner and lowers plasma VWF in vivo.\",\n      \"evidence\": \"CLEC4M-Fc pulldown, cell-based binding/internalization (IF, ELISA), and in vivo hydrodynamic liver transfer in mice\",\n      \"pmids\": [\"23529928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Internalization route and intracellular fate of VWF not detailed in this study\", \"Did not establish receptor recycling versus degradation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided dynamic structural insight into ligand recognition and a virus-driven degradation pathway, showing Man9GlcNAc induces a distinct CRD binding mode/conformation and that KSHV K3/K5 ubiquitin ligases downregulate immature CLEC4M.\",\n      \"evidence\": \"Solution NMR with backbone assignment and 15N relaxation; pulldown, ubiquitylation, flow cytometry, and mutagenesis of trafficking motifs\",\n      \"pmids\": [\"23788638\", \"23460925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CRD flexibility for avidity not quantified\", \"K3/K5 downregulation shown largely in exogenous expression systems\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconciled the endocytic-receptor question at the glycan level, demonstrating CLEC4M CRDs reversibly release mannose glycans and Ca2+ at low pH consistent with endocytic-receptor behavior.\",\n      \"evidence\": \"Solution NMR pH-titration with multiple glycan ligands and calcium\",\n      \"pmids\": [\"24976257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pH-release of isolated CRD not directly linked to cellular endocytic flux\", \"Reconciliation with earlier non-endocytic conclusions context-dependent\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved that CLEC4M's endocytic versus attachment role is pathogen-specific — non-endocytic for phleboviruses but endocytosis-dependent for productive influenza A entry.\",\n      \"evidence\": \"Infection assays with endocytosis-defective L-SIGN mutants in defined cell systems\",\n      \"pmids\": [\"26990254\", \"26763587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch determining endocytic versus tethering outcome per virus unknown\", \"Cytoplasmic-tail trafficking signals not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the structural code for the superior tetramer stability of CLEC4M relative to DC-SIGN, attributing it to a heptad leucine and an arginine–glutamate intra-chain salt bridge that cluster CRDs.\",\n      \"evidence\": \"Gel filtration, DSC, and CD of model polypeptides with uniform repeat units\",\n      \"pmids\": [\"27859859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect of CRD clustering geometry on avidity for natural ligands not directly measured\", \"Designed constructs rather than native receptor\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CLEC4M as a bona fide endocytic clearance receptor for factor VIII, defining the clathrin-dependent route through endosomes to lysosomes and its in vivo effect on plasma FVIII.\",\n      \"evidence\": \"Cell-based binding/internalization, solid-phase binding, clathrin-inhibition pharmacology, in vivo hydrodynamic liver transfer, and IHC\",\n      \"pmids\": [\"30740857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of VWF-dependent versus VWF-independent FVIII uptake in vivo not quantified\", \"Receptor fate after ligand delivery to lysosome not tracked\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CLEC4M as a SARS-CoV-2 receptor on endothelium, binding spike high-mannose glycans/RBD, mediating entry and trans-infection of ACE2+ cells, with potential ACE2 heterodimerization and links to elevated VWF/FVIII in infected liver.\",\n      \"evidence\": \"ELISA/Co-IP binding, siRNA knockdown, pseudovirus and authentic virus infection, glycosylation mutagenesis, confocal microscopy of liver autopsy, and glycomimetic inhibition\",\n      \"pmids\": [\"34341769\", \"34291736\", \"34015061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo role of CLEC4M-ACE2 heterodimerization in SARS-CoV-2 pathogenesis unresolved\", \"Causal link between LSEC infection and elevated VWF/FVIII not mechanistically proven\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Translated the single-residue CRD difference into a selective ligand, designing Man84 whose guanidinium achieves CLEC4M-selective complementarity and, as a dimer, inhibits CLEC4M-dependent trans-infection by SARS-CoV-2 and Ebola.\",\n      \"evidence\": \"X-ray crystallography of CRD/ligand complex, ITC, SPR, NMR, and pseudovirus trans-infection inhibition\",\n      \"pmids\": [\"39246372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and pharmacokinetics of Man84 untested\", \"Selectivity against other C-type lectins not broadly profiled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular switch that determines whether CLEC4M tethers a ligand at the surface versus internalizes it, and the in vivo balance of its antiviral capture versus VWF/FVIII clearance functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined cytoplasmic-tail signal mapped that toggles endocytic versus attachment behavior\", \"Endogenous ligand repertoire beyond VWF, FVIII, and ICAM-3 incompletely cataloged\", \"No structure of the full-length tetrameric receptor engaging a multivalent natural ligand\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 4, 6, 11, 20, 30, 31, 32]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [22, 29]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 23]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 5, 15, 31]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 29]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9, 30, 31, 32]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 8, 27, 29]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VWF\", \"F8\", \"ACE2\", \"ICAM3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}