Autonomous tetramerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR.
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ABSTRACT:
SUBMITTER: Yu QD
PROVIDER: S-EPMC2680971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human dendritic cell-specific intercellular adhesion molecule-1 grabbing nonintegrin, DC-SIGN, and the sinusoidal endothelial cell receptor DC-SIGNR or L-SIGN, are closely related sugar-binding receptors. DC-SIGN acts both as a pathogen-binding endocytic receptor and as a cell adhesion molecule, while DC-SIGNR has only the pathogen-binding function. In addition to differences in the sugar-binding properties of the carbohydrate-recognition domains in the two receptors, there are sequence differences in the adjacent neck domains, which are coiled-coil tetramerization domains comprised largely of 23-amino acid repeat units. A series of model polypeptides consisting of uniform repeat units have been characterized by gel filtration, differential scanning calorimetry and circular dichroism. The results demonstrate that two features characterize repeat units which form more stable tetramers: a leucine reside in the first position of the heptad pattern of hydrophobic residues that pack on the inside of the coiled coil and an arginine residue on the surface of the coiled coil that forms a salt bridge with a glutamic acid residue in the same polypeptide chain. In DC-SIGNR from all primates, very stable repeat units predominate, so the carbohydrate-recognition domains must be held relatively closely together. In contrast, stable repeat units are found only near the membrane in DC-SIGN. The presence of residues that disrupt tetramer formation in repeat units near the carbohydrate-recognition domains of DC-SIGN would allow these domains to splay further apart. Thus, the neck domains of DC-SIGN and DC-SIGNR can contribute to the different functions of these receptors by presenting the sugar-binding sites in different contexts.
| S-EPMC5275740 | biostudies-literature
Project description:Carbohydrate-recognition domains (CRDs) in the glycan-binding receptors DC-SIGN (dendritic-cell-specific intercellular adhesion molecule 1-grabbing nonintegrin; CD209) and DC-SIGNR (DC-SIGN-related receptor, also known as L-SIGN and variously designated CD209L and CD299) are projected from the membrane surface by extended neck domains containing multiple repeats of a largely conserved 23-amino-acid sequence motif. Crystals of a fragment of the neck domain of DC-SIGNR containing multiple repeats in which each molecule extends through multiple unit cells, such that the observed crystallographic asymmetric unit represents one repeat averaged over six repeats of the protein, have been obtained. The repeats are largely alpha-helical. Based on the structure and arrangement of the repeats in the crystal, the neck region can be described as a series of four-helix bundles connected by short, non-helical linkers. Combining the structure of the isolated neck domain with a previously determined overlapping structure of the distal end of the neck region with the CRDs attached provides a model of the almost-complete extracellular portion of the receptor. The results are consistent with previous characterization of the extended structure for the isolated neck region and the extracellular domain. The organization of the neck suggests how CRDs may be disposed differently in DC-SIGN compared with DC-SIGNR and in variant forms of DC-SIGNR assembled from polypeptides with different numbers of repeats in the neck domain.
| S-EPMC2971551 | biostudies-literature
Project description:In the immune system, C-type lectins and CTLDs have been shown to act both as adhesion and as pathogen recognition receptors. The Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and its homologs in human and mouse represent an important C-type lectin family. DC-SIGN contains a lectin domain that recognizes in a Ca2+-dependent manner carbohydrates such as mannose-containing structures present on glycoproteins such as ICAM-2 and ICAM-3. DC-SIGN is a prototype C-type lectin organized in microdomains, which have their role as pathogen recognition receptors in sensing microbes. Although the integrin LFA-1 is a counter-receptor for both ICAM-2 and ICAM-3 on DC, DC-SIGN is the high affinity adhesion receptor for ICAM-2/-3. While cell–cell contact is a primary function of selectins, collectins are specialized in recognition of pathogens. Interestingly, DC-SIGN is a cell adhesion receptor as well as a pathogen recognition receptor. As adhesion receptor, DC-SIGN mediates the contact between dendritic cells (DCs) and T lymphocytes, by binding to ICAM-3, and mediates rolling of DCs on endothelium, by interacting with ICAM-2. As pathogen receptor, DC-SIGN recognizes a variety of microorganisms, including viruses, bacteria, fungi and several parasites (Cambi et al. 2005). The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. In this chapter, we shall focus on the structure and functions of DC-SIGN and related CTLDs in the recognition of pathogens, the molecular and structural determinants that regulate the interaction with pathogen-associated molecular patterns. The heterogeneity of carbohydrate residues exposed on cellular proteins and pathogens regulates specific binding of DC-expressed C-type lectins that contribute to the diversity of immune responses created by DCs (van Kooyk et al. 2003a; Cambi et al. 2005).
| S-EPMC7122914 | biostudies-literature
Project description:BackgroundColon cancer has always been diagnosed at a late stage, which is associated with poor prognosis. The currently used serum tumor markers CEA and CA19-9 display low sensitivity and specificity and may not have diagnostic value in early stage colon cancer. Thus, there is an urgent need to identify novel serum biomarkers for use in the early detection of colon cancer.MethodsIn this study, the expression of DC-SIGN and DC-SIGNR in serum was detected by enzyme-linked immunosorbent assay (ELISA). DC-SIGN and DC-SIGNR expression was detected in cancer tissues by immunohistochemistry (IHC).ResultsThe level of sDC-SIGN was lower in patients than in the healthy controls, while the level of sDC-SIGNR in patients was higher than in the healthy controls. Both sDC-SIGN and sDC-SIGNR had diagnostic significances for cancer patients, and the combined diagnosis of these two markers was higher than both of them alone. Furthermore, there were significant differences between both sDC-SIGN and sDC-SIGNR in stage I/II patients and the healthy controls. Moreover, high sDC-SIGN level was accompanied with the long survival time. Additionally, DC-SIGNR was negative in the cancer foci and matched normal colon tissues but was weakly positive between the cancer foci. DC-SIGN staining was faint in matched normal colon tissues, strong in the tumor stroma and the invasive margin of colon cancer tissues, and negatively correlated with the sDC-SIGN level in serum from the same patient. Interestingly, the percent survival of patients with a DC-SIGN mean density of>0.001219 (the upper 95% confidence interval of matched normal colon tissues) was higher than for all other patients.ConclusionDC-SIGN and DC-SIGNR are blood-based molecular markers that can potentially be used for the diagnosis of early stage patients. Moreover, expression of DC-SIGN in serum and cancer tissues may affect the survival time for colon cancer patients.
| S-EPMC4264775 | biostudies-literature
Project description:Dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGNR are C-type lectins that serve both as cell adhesion and pathogen recognition receptors. Because of the essential role of the these molecules in the immune response, the implication of their alleles in human disease states, and the possible genetic variation at these loci among ethnically diverse populations, we undertook a study to analyze the full extent of DC-SIGN and DC-SIGNR polymorphisms in Caucasian Canadian and indigenous African populations. We report several novel nucleotide variants within regulatory 5'- and 3'-untranslated regions of the genes that could affect their transcription and translation. There were significant differences in the distribution of DC-SIGN and DC-SIGNR alleles among African and non-African populations. Finally, our study clearly demonstrates that Africans show greater genetic diversity at these two closely-related immune loci than observed in other major population groups. The differences may reflect evolutionary pressures generated by environmental factors, such as prevalent pathogens in these geographically distinct regions. Further studies will be needed to determine the net impact of DC-SIGN and DC-SIGNR genetic variants on the expression, translation, and function of the proteins and to understand how these functional polymorphisms may affect immune responses or immune escape.
| S-EPMC7115417 | biostudies-literature
Project description:The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is related with the COVID-19 pandemic. Recent spike protein variations have had an effect on the transmission of the virus. In addition to ACE-2, spike proteins can employ DC-SIGN and its analogous receptor, DC-SIGNR, for host evasion. Spike variations in the DC-SIGN interaction region and role of DC-SIGN in immune evasion have not been well defined. To understand the spike protein variations and their binding mode, phylogenetic analysis of the complete GISAID (Global Initiative for Sharing Avian Influenza Data) data of the SARS-CoV-2 spike protein was considered. In addition, an in silico knockout network evaluation of the SARS-CoV-2 single-cell transcriptome was conducted to determine the key role of DC-SIGN/R in immunological dysregulation. Within the DC-SIGN-interacting region of the SARS-CoV spike protein, the spike protein of SARS-CoV-2 displayed remarkable similarity to the SARS-CoV spike protein. Surprisingly, the phylogenetic analysis revealed that the SARS-CoV-2's spike exhibited significantly diverse variants in the DC-SIGN interaction domain, which altered the frequency of these variants. The variation within the DC-SIGN-interacting domain of spike proteins affected the binding of a limited number of variants with DC-SIGN and DC-SIGNR and affected their evolution. MMGBSA binding free energies evaluation differed for variants from those of the wild type, suggesting the influence of substitution mutations on the interaction pattern. In silico knockout network analysis of the single-cell transcriptome of Bronchoalveolar Lavage and peripheral blood mononuclear cells revealed that SARS-CoV-2 altered DC-SIGN/R signaling. Early surveillance of diverse SARS-CoV-2 strains could preclude a worsening of the pandemic and facilitate the development of an optimum vaccine against variations. The spike Receptor Binding Domain genetic variants are thought to boost SARS CoV-2 immune evasion, resulting in its higher longevity.Supplementary informationThe online version contains supplementary material available at 10.1007/s13337-023-00820-3.
| S-EPMC10206574 | biostudies-literature
Project description:Dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a member of the C-type lectin family selectively expressed on immune-related cells. In the present study, we performed a systematic interaction analysis of DC-SIGN and its related receptors, DC-SIGN-related protein (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin) using frontal affinity chromatography (FAC). Carbohydrate-recognition domains of the lectins, expressed as Fc-fusion chimeras, were immobilized to Protein A-Sepharose and subjected to quantitative FAC analysis using 157 pyridylaminated glycans. Both DC-SIGN-Fc and DC-SIGNR-Fc showed similar specificities for glycans containing terminal mannose and fucose, but great difference in affinity under the given experimental conditions. By contrast, LSECtin-Fc showed no affinity to these glycans. As a common feature, the DC-SIGN-related lectin-Fc chimeras, including LSECtin, exhibited binding affinity to mono- and/or bi-antennary agalactosylated N-glycans. The detailed FAC analysis further implied that the presence of terminal GlcNAc at the N-acetylglucosaminyltransferase I position is a key determinant for the binding of these lectins to agalactosylated N-glycans. By contrast, none of the lectins showed significant affinity to highly branched agalactosylated N-glycans. All of the lectins expressed on the cells were able to mediate cellular adhesion to agalactosylated cells and endocytosis of a model glycoprotein, agalactosylated α1-acid glycoprotein. In this context, we also identified three agalactosylated serum glycoproteins recognized by DC-SIGN-Fc (i.e. α-2-macroglobulin, serotransferrin and IgG heavy chain), by lectin blotting and MS analysis. Hence, we propose that 'agalactosylated N-glycans' are candidate ligands common to these lectins.
| S-EPMC7163941 | biostudies-literature
Project description:In follicular lymphoma (FL), surface immunoglobulin (sIg) carries mandatory N-glycosylation sites in the variable regions, inserted during somatic hypermutation. These glycosylation sites are tumor-specific, indicating a critical function in FL. Added glycan unexpectedly terminates at high mannose (Mann) and confers capability for sIg-mediated interaction with local macrophage-expressed DC-SIGN lectin resulting in low-level activation of upstream B-cell receptor signaling responses. Here we show that despite being of low-level, DC-SIGN induces a similar downstream transcriptional response to anti-IgM in primary FL cells, characterized by activation of pathways associated with B-cell survival, proliferation and cell-cell communication. Lectin binding was also able to engage post-transcriptional receptor cross-talk pathways since, like anti-IgM, DC-SIGN down-modulated cell surface expression of CXCR4. Importantly, pre-exposure of a FL-derived cell line expressing sIgM-Mann or primary FL cells to DC-SIGN, which does not block anti-IgM binding, reversibly paralyzed the subsequent Ca2+ response to anti-IgM. These novel findings indicate that modulation of sIg function occurs in FL via lectin binding to acquired mannoses. The B-cell receptor alternative engagement described here provides two advantages to lymphoma cells: (i) activation of signaling, which, albeit of low-level, is sufficient to trigger canonical lymphoma-promoting responses, and (ii) protection from exogenous antigen by paralyzing anti-IgM-induced signaling. Blockade of this alternative engagement could offer a new therapeutic strategy.
| S-EPMC8175722 | biostudies-literature
Project description:As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelium and endothelium. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor binding domain (S-RBD) or S1 encompassing both NTB and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two N-glycosylation sequons, at sites N92 and N361, but we determined that only site N92 is occupied. Removal of the N-glycosylation at this site enhances the binding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting a role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry and infection in cell types where both are present. Furthermore, we demonstrate that human endothelial cells are permissive to SARS-CoV-2 infection and interference with CD209L activity by knockdown strategy or with soluble CD209L inhibits virus entry. Our observations demonstrate that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This property is particularly important in tissues where ACE2 has low expression or is absent, and may have implications for antiviral drug development.
| S-EPMC7325172 | biostudies-literature
Project description:As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelia and endothelia. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor-binding domain (S-RBD) or S1 encompassing both N termal domain and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two N-glycosylation sequons, at sites N92 and N361, but we determined that only site N92 is occupied. Removal of the N-glycosylation at this site enhances the binding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting a role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry and infection in cell types where both are present. Furthermore, we demonstrate that human endothelial cells are permissive to SARS-CoV-2 infection, and interference with CD209L activity by a knockdown strategy or with soluble CD209L inhibits virus entry. Our observations demonstrate that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This property is particularly important in tissues where ACE2 has low expression or is absent and may have implications for antiviral drug development.
| S-EPMC8265543 | biostudies-literature