Oligolysine-based Oligosaccharide Clusters

Frison, Natacha; Taylor, Maureen E.; Soilleux, Elizabeth; Bousser, Marie-Thérèse; Mayer, Roger; Monsigny, Michel; Drickamer, Kurt; Roche, Annie‐Claude

doi:10.1074/jbc.m302483200

Cited by 115 publications

(59 citation statements)

References 40 publications

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“…We observed two distinct states among the truncated receptors, the monomeric CRD, R8, R7, and R5 constructs of DC-SIGN and DC-SIGNR, as well as the tetrameric full-length extracellular construct, by using both size exclusion chromatography and the analytic ultracentrifugation technique. DC-SIGN and DC-SIGNR have been shown to selectively bind branched high-mannose carbohydrate (8,9). The increased gp120 binding affinity of the tetrameric DC-SIGN/R compared to the shorter and monomeric receptors is most likely an avidity effect in which the tetrameric receptor is capable of recognizing multiple high-mannose carbohydrates found on the heavily glycosylated target molecule HIV-1 gp120.…”

Section: Discussionmentioning

confidence: 99%

Characterization of DC-SIGN/R Interaction with Human Immunodeficiency Virus Type 1 gp120 and ICAM Molecules Favors the Receptor's Role as an Antigen-Capturing Rather than an Adhesion Receptor

Snyder

Ford

Torabi‐Parizi

et al. 2005

J Virol

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The dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin binding receptor (DC-SIGN) was shown to bind human immunodeficiency virus type 1 (HIV-1) viral envelope protein gp120 and proposed to function as a Trojan horse to enhance trans-virus infection to host T cells. To better understand the mechanism by which DC-SIGN and DC-SIGNR selectively bind HIV-1 gp120, we constructed a series of deletion mutations in the repeat regions of both receptors. Different truncated receptors exist in different oligomeric forms. The carbohydrate binding domain without any repeats was monomeric, whereas the full extracellular receptors existed as tetramers. All reconstituted receptors retained their ability to bind gp120. The dissociation constant, however, differed drastically from micromolar values for the monomeric receptors to nanomolar values for the tetrameric receptors, suggesting that the repeat region of these receptors contributes to the avidity of gp120 binding. Such oligomerization may provide a mechanism for the receptor to selectively recognize pathogens containing multiple high-mannose-concentration carbohydrates. In contrast, the receptors bound to ICAMs with submicromolar affinities that are similar to those of two nonspecific cell surface glycoproteins, Fc␥RIIb and Fc␥RIII, and the oligomerization of DC-SIGNR resulted in no increase in binding affinity to ICAM-3. These findings suggest that DC-SIGN may not discriminate other cell surface glycoproteins from ICAM-3 binding. The pH dependence in DC-SIGN binding to gp120 showed that the receptor retained high-affinity gp120 binding at neutral pH but lost gp120 binding at pH 5, suggesting a release mechanism of HIV in the acidic endosomal compartment by DC-SIGN. Our work contradicts the function of DC-SIGN as a Trojan horse to facilitate HIV-1 infection; rather, it supports the function of DC-SIGN/R (a designation referring to both DC-SIGN and DC-SIGNR) as an antigen-capturing receptor.

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Section: Discussionmentioning

confidence: 99%

Characterization of DC-SIGN/R Interaction with Human Immunodeficiency Virus Type 1 gp120 and ICAM Molecules Favors the Receptor's Role as an Antigen-Capturing Rather than an Adhesion Receptor

Snyder

Ford

Torabi‐Parizi

et al. 2005

J Virol

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“…Unfortunately, studies on DC-SIGN-oligosaccharide interactions have mainly focused on defining ligands for DC-SIGN using synthetic oligosaccharides or purified glycopeptides (4,5,15). Little information is known on the influence of receptor oligomerization on ligand binding, especially on binding of native ligands such as HIV gp120.…”

Section: Discussionmentioning

confidence: 99%

“…CLRs expressed by DCs include the mannose receptor (CD206), DEC-205 (CD205), Langerin (CD207), and DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN; CD209) (3). These receptors differ not only in their expression on various subsets of DCs and other tissues, but they also recognize different oligosaccharides thus discriminating between different ligands (3,4).…”

mentioning

confidence: 99%

Proteomic Analysis of DC-SIGN on Dendritic Cells Detects Tetramers Required for Ligand Binding but No Association with CD4

Bernhard

Lai

Wilkinson

et al. 2004

Journal of Biological Chemistry

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DC-SIGN (dendritic cell specific intracellular adhesion molecule 3 grabbing non-integrin) or CD209 is a type II transmembrane protein and one of several Ctype lectin receptors expressed by dendritic cell subsets, which bind to high mannose glycoproteins promoting their endocytosis and potential degradation. DC-SIGN also mediates attachment of HIV to dendritic cells and binding to this receptor can subsequently lead to endocytosis or enhancement of CD4/CCR5-dependent infection. The latter was proposed to be facilitated by an interaction between DC-SIGN and CD4. Endocytosis of HIV virions does not necessarily lead to their complete degradation. A proportion of the virions remain infective and can be later presented to T cells mediating their infection in trans. Previously, the extracellular domain of recombinant DC-SIGN has been shown to assemble as tetramers and in the current study we use a short range covalent cross-linker and show that DC-SIGN exists as tetramers on the surface of immature monocyte-derived dendritic cells. There was no evidence of direct binding between DC-SIGN and CD4 either by cross-linking or by fluorescence resonance energy transfer measurements suggesting that there is no constitutive association of the majority of these proteins in the membrane. Importantly we also show that the tetrameric complexes, in contrast to DC-SIGN monomers, bind with high affinity to high mannose glycoproteins such as mannan or HIV gp120 suggesting that such an assembly is required for high affinity binding of glycoproteins to DC-SIGN, providing the first direct evidence that DC-SIGN tetramers are essential for high affinity interactions with pathogens like HIV.

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“…Although the oligosaccharide ligands recognized by DC-SIGN and DC-SIGNR are found on host cells, they are probably more highly clustered on the surfaces of viruses and parasites. Thus, it is likely that the organization of these receptors enhances the affinity for targets that contain appropriately high densities of specific carbohydrate ligands (10,11).…”

mentioning

confidence: 99%

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

Feinberg

Guo

Mitchell

et al. 2005

Journal of Biological Chemistry

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218

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The human cell surface receptors DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin) and DC-SIGNR (DC-SIGN-related) bind to oligosaccharide ligands found on human tissues as well as on pathogens including viruses, bacteria, and parasites. The extracellular portion of each receptor contains a membrane-distal carbohydrate-recognition domain (CRD) and forms tetramers stabilized by an extended neck region consisting of 23 amino acid repeats. Cross-linking analysis of full-length receptors expressed in fibroblasts confirms the tetrameric state of the intact receptors. Hydrodynamic studies on truncated receptors demonstrate that the portion of the neck of each protein adjacent to the CRD is sufficient to mediate the formation of dimers, whereas regions near the N terminus are needed to stabilize the tetramers. Some of the intervening repeats are missing from polymorphic forms of DC-SIGNR. Two different crystal forms of truncated DC-SIGNR comprising two neck repeats and the CRD reveal that the CRDs are flexibly linked to the neck, which contains ␣-helical segments interspersed with non-helical regions. Differential scanning calorimetry measurements indicate that the neck and CRDs are independently folded domains. Based on the crystal structures and hydrodynamic data, models for the full extracellular domains of the receptors have been generated. The observed flexibility of the CRDs in the tetramer, combined with previous data on the specificity of these receptors, suggests an important role for oligomerization in the recognition of endogenous glycans, in particular those present on the surfaces of enveloped viruses recognized by these proteins.The dendritic cell receptor DC-SIGN 1 and the closely related DC-SIGNR found on endothelial cells have been of considerable interest because of their ability to enhance infection of T cells by the human immunodeficiency virus and because of their interactions with glycoproteins found on the surface of other enveloped viruses (1, 2). The physiological functions of these receptors are not known with certainty, but DC-SIGN has been ascribed roles in binding to intercellular adhesion molecule 3 on T cells and intercellular adhesion molecule 2 on endothelia, as well as in uptake of pathogens (3-7). Although DC-SIGN binds to a broad spectrum of glycans, it has highest affinity for N-linked high mannose oligosaccharides and fucose-containing structures that are found both as blood group antigens in human tissues and on the surfaces of certain parasites (7,8). DC-SIGNR binds only to the high mannose oligosaccharides, and unlike DC-SIGN, it does not mediate uptake and degradation of glycoconjugates (8).DC-SIGN and DC-SIGNR share nearly 80% sequence identity and are closely similar in overall architecture. Both receptors are type II transmembrane proteins in which C-terminal C-type carbohydrate-recognition domains (CRDs) are projected from the cell surface by a neck comprising a series of highly conserved 23-amino acid repeats. There are seven complete re...

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Oligolysine-based Oligosaccharide Clusters

Cited by 115 publications

References 40 publications

Characterization of DC-SIGN/R Interaction with Human Immunodeficiency Virus Type 1 gp120 and ICAM Molecules Favors the Receptor's Role as an Antigen-Capturing Rather than an Adhesion Receptor

Characterization of DC-SIGN/R Interaction with Human Immunodeficiency Virus Type 1 gp120 and ICAM Molecules Favors the Receptor's Role as an Antigen-Capturing Rather than an Adhesion Receptor

Proteomic Analysis of DC-SIGN on Dendritic Cells Detects Tetramers Required for Ligand Binding but No Association with CD4

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

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