Affinage

CLEC4M

C-type lectin domain family 4 member M · UniProt Q9H2X3

Length
399 aa
Mass
45.4 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2001 High

    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

    PMID:11384997 PMID:11739956

    Open questions at the time
    • Did not address receptor behavior in the context of full-length receptor on cells
    • Endogenous physiological ligands not yet defined
  2. 2001 High

    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

    PMID:11226297

    Open questions at the time
    • Mechanism distinguishing capture from productive entry not resolved
    • Did not establish whether CLEC4M endocytoses or merely tethers virus
  3. 2004 High

    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

    PMID:15184372 PMID:15195147

    Open questions at the time
    • The non-endocytic conclusion was later shown to be virus-context dependent
    • Did not map full repertoire of physiological glycoprotein ligands
  4. 2004 High

    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

    PMID:15254204 PMID:15371595 PMID:15496474

    Open questions at the time
    • Relative contribution of CLEC4M versus other receptors in vivo not quantified
    • Trafficking route of internalized virus only partially characterized
  5. 2004 High

    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

    PMID:15509576 PMID:15784257

    Open questions at the time
    • Did not connect neck length variation to in vivo function
    • Full-length extracellular domain structure not yet solved
  6. 2005 High

    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

    PMID:16369534

    Open questions at the time
    • Causal mechanism connecting homozygosity to enhanced degradation not fully defined
    • Association not separated from linked loci
  7. 2006 High

    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

    PMID:16413044 PMID:16621794

    Open questions at the time
    • Physiological consequence of hetero-oligomer formation unresolved
    • Did not test endogenous ligand binding across alleles
  8. 2006 High

    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

    PMID:16415006

    Open questions at the time
    • Specific CRD residues responsible not pinpointed
    • In vivo relevance to WNV pathogenesis untested
  9. 2007 Medium

    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

    PMID:17250696 PMID:17715238

    Open questions at the time
    • Physiological/allergic relevance of CLEC4M shedding not established
    • ICAM-3 as an endogenous ligand only indirectly assessed
  10. 2009 High

    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

    PMID:19249311 PMID:19833723 PMID:19835887

    Open questions at the time
    • Why CLEC4M fails to transmit HIV-1 despite binding gp120 not fully reconciled mechanistically
    • Single-residue rescue (K270W) insufficient, indicating additional determinants unidentified
  11. 2010 High

    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

    PMID:21191006

    Open questions at the time
    • Strain-dependence (H1N1 inefficiency) not mechanistically dissected
    • In vivo contribution to influenza tropism untested
  12. 2011 Medium

    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

    PMID:22090124

    Open questions at the time
    • Intracellular signaling intermediates linking CRD engagement to ERK not identified
    • Single cell-line system without primary DC validation
  13. 2013 High

    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

    PMID:23529928

    Open questions at the time
    • Internalization route and intracellular fate of VWF not detailed in this study
    • Did not establish receptor recycling versus degradation
  14. 2013 Medium

    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

    PMID:23460925 PMID:23788638

    Open questions at the time
    • Functional consequence of CRD flexibility for avidity not quantified
    • K3/K5 downregulation shown largely in exogenous expression systems
  15. 2014 Medium

    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

    PMID:24976257

    Open questions at the time
    • pH-release of isolated CRD not directly linked to cellular endocytic flux
    • Reconciliation with earlier non-endocytic conclusions context-dependent
  16. 2016 High

    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

    PMID:26763587 PMID:26990254

    Open questions at the time
    • Molecular switch determining endocytic versus tethering outcome per virus unknown
    • Cytoplasmic-tail trafficking signals not mapped
  17. 2016 High

    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

    PMID:27859859

    Open questions at the time
    • Effect of CRD clustering geometry on avidity for natural ligands not directly measured
    • Designed constructs rather than native receptor
  18. 2019 High

    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

    PMID:30740857

    Open questions at the time
    • Relative contribution of VWF-dependent versus VWF-independent FVIII uptake in vivo not quantified
    • Receptor fate after ligand delivery to lysosome not tracked
  19. 2021 High

    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

    PMID:34015061 PMID:34291736 PMID:34341769

    Open questions at the time
    • 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
  20. 2024 High

    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

    PMID:39246372

    Open questions at the time
    • In vivo efficacy and pharmacokinetics of Man84 untested
    • Selectivity against other C-type lectins not broadly profiled

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 8 GO:0008289 lipid binding 3 GO:0038024 cargo receptor activity 2 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-109582 Hemostasis 2 R-HSA-168256 Immune System 2
Partners
ACE2F8ICAM3VWF

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. X-ray crystallography of CRD-oligosaccharide complexes combined with binding studies Science High 11739956
2001 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. Chemical cross-linking, equilibrium ultracentrifugation, circular dichroism, binding assays with recombinant fragments The Journal of biological chemistry High 11384997
2001 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. Cell-based trans-infection assay, carbohydrate competition, immunostaining Proceedings of the National Academy of Sciences of the United States of America High 11226297
2004 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. Glycan array screening, structural analysis, mutagenesis, pH-dependent ligand-release assays, endocytosis assays Nature structural & molecular biology High 15195147
2004 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. cDNA library screen, retroviral pseudotype infection assay, RT-PCR for viral replication, transfection and infection of CHO cells, immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America High 15496474
2004 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. Chemical cross-linking of full-length receptor in fibroblasts, hydrodynamic analysis, X-ray crystallography of truncated constructs, differential scanning calorimetry The Journal of biological chemistry High 15509576
2004 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. HCV pseudovirus entry assay, co-culture transinfection assay, inhibitor studies (mannan, EGTA, antibodies) Proceedings of the National Academy of Sciences of the United States of America High 15371595
2004 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. Binding assays with neoglycoconjugates, site-directed mutagenesis, molecular modeling and docking The Journal of biological chemistry High 15184372
2004 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. Cell-based internalization assays, confocal microscopy of intracellular HCV trafficking, antibody blocking Journal of virology Medium 15254204
2005 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. Genetic association study combined with cell-based binding assays, viral degradation assays, and trans-infection assays on homozygous vs. heterozygous cells Nature genetics High 16369534
2005 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. X-ray crystallography, homology modeling Journal of molecular biology High 15784257
2006 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. Chimeric receptor analysis, infection assays in transfected cells, virus binding affinity measurements Journal of virology High 16415006
2006 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. Viral infection enhancement assays, tetramerization assays, coexpression experiments Virology Medium 16413044
2006 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. Chemical cross-linking, analytical ultracentrifugation, affinity-tagging approach, transfected fibroblast expression The Journal of biological chemistry High 16621794
2007 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. Site-directed mutagenesis of glycosylation sites on spike protein, pseudovirus infection assays in DC/L-SIGN-expressing cells Journal of virology High 17715238
2007 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. In silico substrate prediction (PoPS), cell-surface cleavage assays, purified recombinant protein digestion, N-terminal sequencing, MALDI mass spectrometry, ICAM-3 binding assay Clinical and experimental allergy Medium 17250696
2008 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). Binding affinity measurements, virion capture assays, pH-dependent ligand release assays, co-expression immunostaining Virology Medium 18083206
2009 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. Gel filtration, differential scanning calorimetry, circular dichroism, isolated neck domain expression Journal of molecular biology High 19249311
2009 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. X-ray crystallography of multi-repeat neck fragment Journal of molecular biology High 19835887
2009 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. DC-SIGN/L-SIGN chimera analysis in Raji B cells, site-directed mutagenesis, trans-infection assays The Journal of biological chemistry High 19833723
2010 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. Infection assay in sialic-acid-deficient CHO cells expressing DC-SIGN or L-SIGN, mannan competition, Ca2+ chelation, bacterial neuraminidase controls Journal of virology High 21191006
2011 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. Surface plasmon resonance, ERK phosphorylation assay in transfected cells, antibody neutralization, cytokine measurement Journal of virology Medium 22090124
2013 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. CLEC4M-Fc pulldown, cell-based binding and internalization assays (immunofluorescence, ELISA), in vivo hydrodynamic liver transfer in mice Blood High 23529928
2013 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. Solution-state NMR spectroscopy, backbone assignment, 15N relaxation measurements The Journal of biological chemistry High 23788638
2013 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. Pulldown assays, ubiquitylation assays, flow cytometry (surface expression), mutagenesis of trafficking motifs, viral infection experiments PloS one Medium 23460925
2014 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. Solution NMR pH titration experiments with multiple glycan ligands and calcium The FEBS journal Medium 24976257
2016 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. Infection assays with endocytosis-defective L-SIGN mutants, virus binding assays Traffic Medium 26990254
2016 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. Infection assays in sialic acid-deficient Lec2 CHO cells expressing wild-type or endocytosis-defective DC-SIGN/L-SIGN mutants Scientific reports High 26763587
2016 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. Gel filtration, differential scanning calorimetry, circular dichroism of model polypeptides with uniform repeat units Protein science High 27859859
2019 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. Cell-based binding and internalization assays, solid-phase binding assay, in vivo hydrodynamic liver transfer, immunohistochemistry, pharmacological inhibition of clathrin-dependent endocytosis Journal of thrombosis and haemostasis High 30740857
2021 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. Multiple biochemical binding assays (ELISA, co-immunoprecipitation), siRNA knockdown, pseudovirus and authentic virus infection assays, N-glycosylation mutagenesis, immunofluorescence ACS central science High 34341769
2021 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. High-resolution confocal microscopy of liver autopsy samples, pseudovirus and authentic virus infection assays, L-SIGN blocking experiments, immunofluorescence JCI insight High 34291736
2021 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. Pseudovirus and authentic SARS-CoV-2 trans-infection assays, glycomimetic inhibitor competition, human respiratory cell lines PLoS pathogens High 34015061
2024 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. X-ray crystallography of CRD/ligand complex, ITC binding measurements, SPR, NMR conformational analysis, pseudovirus trans-infection inhibition assay Chemical science High 39246372

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science (New York, N.Y.) 553 11739956
2002 C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. Journal of virology 519 12050398
2004 Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nature structural & molecular biology 477 15195147
2004 CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proceedings of the National Academy of Sciences of the United States of America 459 15496474
2001 A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. The Journal of biological chemistry 417 11384997
2004 DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. Journal of virology 304 15479853
2003 DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. The Journal of biological chemistry 300 12609975
2003 DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 299 12504546
2003 Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. Journal of virology 294 12634366
2006 West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. Journal of virology 281 16415006
2001 DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proceedings of the National Academy of Sciences of the United States of America 271 11226297
2000 DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. Journal of immunology (Baltimore, Md. : 1950) 215 10975799
2003 L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proceedings of the National Academy of Sciences of the United States of America 214 12676990
2021 CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2. ACS central science 213 34341769
2003 Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. Journal of virology 201 12502850
2003 DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. Journal of virology 192 14581539
2004 L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proceedings of the National Academy of Sciences of the United States of America 160 15371595
2004 Extended neck regions stabilize tetramers of the receptors DC-SIGN and DC-SIGNR. The Journal of biological chemistry 154 15509576
2021 DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist. PLoS pathogens 151 34015061
2004 C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles. The Journal of biological chemistry 147 15166245
2005 Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nature genetics 120 16369534
2008 DC-SIGN and L-SIGN: the SIGNs for infection. Journal of molecular medicine (Berlin, Germany) 117 18458800
2004 Hepatitis C virus targets DC-SIGN and L-SIGN to escape lysosomal degradation. Journal of virology 111 15254204
2007 Specific asparagine-linked glycosylation sites are critical for DC-SIGN- and L-SIGN-mediated severe acute respiratory syndrome coronavirus entry. Journal of virology 109 17715238
2010 N-linked glycosylation facilitates sialic acid-independent attachment and entry of influenza A viruses into cells expressing DC-SIGN or L-SIGN. Journal of virology 107 21191006
2013 The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels. Blood 97 23529928
2021 CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. bioRxiv : the preprint server for biology 90 32607506
2004 Molecular basis of the differences in binding properties of the highly related C-type lectins DC-SIGN and L-SIGN to Lewis X trisaccharide and Schistosoma mansoni egg antigens. The Journal of biological chemistry 84 15184372
2006 Expression of DC-SIGN and DC-SIGNR on human sinusoidal endothelium: a role for capturing hepatitis C virus particles. The American journal of pathology 78 16816373
2011 Respiratory syncytial virus glycoprotein G interacts with DC-SIGN and L-SIGN to activate ERK1 and ERK2. Journal of virology 73 22090124
2003 DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin) and DC-SIGN-related (DC-SIGNR): friend or foe? Clinical science (London, England : 1979) 71 12653690
2007 Analysis of the interaction of Ebola virus glycoprotein with DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) and its homologue DC-SIGNR. The Journal of infectious diseases 70 17940955
2004 Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1. Immunobiology 68 15481146
2020 C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors. Biology 64 33375175
2007 The protease allergen Der p 1 cleaves cell surface DC-SIGN and DC-SIGNR: experimental analysis of in silico substrate identification and implications in allergic responses. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 64 17250696
2008 Interactions of LSECtin and DC-SIGN/DC-SIGNR with viral ligands: Differential pH dependence, internalization and virion binding. Virology 60 18083206
2016 Differential Use of the C-Type Lectins L-SIGN and DC-SIGN for Phlebovirus Endocytosis. Traffic (Copenhagen, Denmark) 59 26990254
2013 DC-SIGN, DC-SIGNR and LSECtin: C-type lectins for infection. International reviews of immunology 56 24156700
2002 Primary isolated human brain microvascular endothelial cells express diverse HIV/SIV-associated chemokine coreceptors and DC-SIGN and L-SIGN. Virology 55 12083838
2015 CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. Journal of thrombosis and haemostasis : JTH 52 25832887
2007 The C type lectins DC-SIGN and L-SIGN: receptors for viral glycoproteins. Methods in molecular biology (Clifton, N.J.) 48 17502670
2017 Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis. Journal of hematology & oncology 45 28109307
2002 The role of DC-SIGN and DC-SIGNR in HIV and Ebola virus infection: can potential therapeutics block virus transmission and dissemination? Expert opinion on therapeutic targets 45 12223058
2016 Endocytic function is critical for influenza A virus infection via DC-SIGN and L-SIGN. Scientific reports 43 26763587
2006 Internalizing antibodies to the C-type lectins, L-SIGN and DC-SIGN, inhibit viral glycoprotein binding and deliver antigen to human dendritic cells for the induction of T cell responses. Journal of immunology (Baltimore, Md. : 1950) 41 16365436
2019 The endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manner. Journal of thrombosis and haemostasis : JTH 40 30740857
2014 The clinical significance of DC-SIGN and DC-SIGNR, which are novel markers expressed in human colon cancer. PloS one 39 25504222
2017 DC - SIGNR by influencing the lncRNA HNRNPKP2 upregulates the expression of CXCR4 in gastric cancer liver metastasis. Molecular cancer 38 28403883
2021 L-SIGN is a receptor on liver sinusoidal endothelial cells for SARS-CoV-2 virus. JCI insight 37 34291736
2014 Distinct usage of three C-type lectins by Japanese encephalitis virus: DC-SIGN, DC-SIGNR, and LSECtin. Archives of virology 37 24623090
2007 The polymorphisms in DC-SIGNR affect susceptibility to HIV type 1 infection. AIDS research and human retroviruses 37 17530994
2011 Role of DC-SIGN and L-SIGN receptors in HIV-1 vertical transmission. Human immunology 30 21277928
2010 Frontal affinity chromatography analysis of constructs of DC-SIGN, DC-SIGNR and LSECtin extend evidence for affinity to agalactosylated N-glycans. The FEBS journal 30 20840590
2013 Utilization of human DC-SIGN and L-SIGN for entry and infection of host cells by the New World arenavirus, Junín virus. Biochemical and biophysical research communications 29 24183720
2005 The structure of DC-SIGNR with a portion of its repeat domain lends insights to modeling of the receptor tetramer. Journal of molecular biology 28 15784257
2005 Role of the C-type lectins DC-SIGN and L-SIGN in Leishmania interaction with host phagocytes. Immunobiology 28 16164025
2003 Isolation and characterization of the human DC-SIGN and DC-SIGNR promoters. Gene 28 12957386
2002 Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity. Human pathology 27 12152166
2009 Autonomous tetramerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR. Journal of molecular biology 26 19249311
2003 The tandem-repeat polymorphism of the DC-SIGNR gene does not affect the susceptibility to HIV infection and the progression to AIDS. Clinical immunology (Orlando, Fla.) 26 12738250
2009 Segmented helical structure of the neck region of the glycan-binding receptor DC-SIGNR. Journal of molecular biology 25 19835887
2012 Expression of the C-type lectins DC-SIGN or L-SIGN alters host cell susceptibility for the avian coronavirus, infectious bronchitis virus. Veterinary microbiology 24 22340967
2007 The C-type lectin L-SIGN differentially recognizes glycan antigens on egg glycosphingolipids and soluble egg glycoproteins from Schistosoma mansoni. Glycobiology 24 17621595
2006 Impact of polymorphisms in the DC-SIGNR neck domain on the interaction with pathogens. Virology 24 16413044
2009 HIV-1 transmission by dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is regulated by determinants in the carbohydrate recognition domain that are absent in liver/lymph node-SIGN (L-SIGN). The Journal of biological chemistry 23 19833723
2008 Branched oligosaccharide structures on HBV prevent interaction with both DC-SIGN and L-SIGN. Journal of viral hepatitis 23 18482282
2007 DC-SIGN and DC-SIGNR genetic diversity among different ethnic populations: potential implications for pathogen recognition and disease susceptibility. Human immunology 23 17509452
2009 Functional genetic variants in DC-SIGNR are associated with mother-to-child transmission of HIV-1. PloS one 22 19809496
2007 Role of homozygous DC-SIGNR 5/5 tandem repeat polymorphism in HIV-1 exposed seronegative North Indian individuals. Journal of clinical immunology 21 17876530
2005 Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms. European journal of human genetics : EJHG 20 15812562
2013 Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR. PloS one 18 23460925
2013 Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR protein reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments. The Journal of biological chemistry 18 23788638
2006 The tandem-repeat polymorphism of the DC-SIGNR gene in HCV infection. Journal of viral hepatitis 17 16364081
2002 Molecular characterization of the murine SIGNR1 gene encoding a C-type lectin homologous to human DC-SIGN and DC-SIGNR. Gene 17 12137941
2023 The contribution of the sinusoidal endothelial cell receptors CLEC4M, stabilin-2, and SCARA5 to VWF-FVIII clearance in thrombosis and hemostasis. Journal of thrombosis and haemostasis : JTH 15 37085036
2021 Expression of the human or porcine C-type lectins DC-SIGN/L-SIGN confers susceptibility to porcine epidemic diarrhea virus entry and infection in otherwise refractory cell lines. Microbial pathogenesis 15 34022357
2016 DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans. Journal of virology 15 27334579
2006 All but the shortest polymorphic forms of the viral receptor DC-SIGNR assemble into stable homo- and heterotetramers. The Journal of biological chemistry 15 16621794
2008 Interaction of acute lymphopblastic leukemia cells with C-type lectins DC-SIGN and L-SIGN. Experimental hematology 13 18375037
2011 Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements. Biochemistry 12 21650186
2010 The nine-repeat DC-SIGNR isoform is associated with increased HIV-RNA loads and HIV sexual transmission. Journal of clinical immunology 12 20217198
2022 Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy? AJNR. American journal of neuroradiology 11 35589136
2015 Characterization of the duplicate L-SIGN and DC-SIGN genes in miiuy croaker and evolutionary analysis of L-SIGN in fishes. Developmental and comparative immunology 11 25596146
2021 Epigenetic glycosylation of SARS-CoV-2 impact viral infection through DC&L-SIGN receptors. iScience 10 34786539
2018 Genetic variation in the C-type lectin receptor CLEC4M in type 1 von Willebrand Disease patients. PloS one 10 29389944
2005 Determination of DC-SIGN and DC-SIGNR repeat region variations. Methods in molecular biology (Clifton, N.J.) 10 16061998
2014 NMR evidence for oligosaccharide release from the dendritic-cell specific intercellular adhesion molecule 3-grabbing non-integrin-related (CLEC4M) carbohydrate recognition domain at low pH. The FEBS journal 9 24976257
2016 Oligomerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR: Sequence variation and stability differences. Protein science : a publication of the Protein Society 8 27859859
2012 Polymorphisms in DC-SIGN and L-SIGN genes are associated with HIV-1 vertical transmission in a Northeastern Brazilian population. Human immunology 8 22902397
2012 The VNTR polymorphism of the DC-SIGNR gene and susceptibility to HIV-1 infection: a meta-analysis. PloS one 8 22957026
2010 Influence of polymorphism in dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related (DC-SIGNR) gene on HIV-1 trans-infection. Biochemical and biophysical research communications 8 20152818
2006 L-SIGN (CD209L) isoforms differently mediate trans-infection of hepatoma cells by hepatitis C virus pseudoparticles. The Journal of general virology 8 16894195
2024 Unprecedented selectivity for homologous lectin targets: differential targeting of the viral receptors L-SIGN and DC-SIGN. Chemical science 7 39246372
2012 The origin and evolution of variable number tandem repeat of CLEC4M gene in the global human population. PloS one 7 22279577
2006 [Analysis of DC-SIGN and DC-SIGNR genetic polymorphism in Chinese Han population]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 6 16883544
2023 SARS CoV-2 spike protein variants exploit DC-SIGN/DC-SIGNR receptor for evolution and severity: an in-silico insight. Virusdisease 5 37363363
2013 Interaction of L-SIGN with hepatitis C virus envelope protein E2 up-regulates Raf-MEK-ERK pathway. Cell biochemistry and biophysics 5 23292357
2014 CLEC4M-positive and CD81-negative Huh7 cells are not susceptible to JFH-1 HCVcc infection but mediate transinfection. Archives of virology 4 24965233
2013 The DC-SIGNR 7/5 genotype is associated with high dendritic cell counts and their subsets in patients infected with HIV-1. Journal of clinical immunology 4 23354840
2008 [DC-SIGNR polymorphisms and its association with HIV-1 infection]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 4 18841568

Missed literature

Know a paper Affinage missed for CLEC4M? Flag it for the maintainers and the community.

No submissions yet.