48 results found
Jégouzo SAF, Feinberg H, Morrison A, et al., 2019, CD23 is a glycan-binding receptor in some mammalian species, Journal of Biological Chemistry, Vol: 294, Pages: 14845-14859, ISSN: 0021-9258
CD23, the low affinity IgE receptor found on B lymphocytes and other cells, contains a C-terminal lectin-like domain that resembles C-type carbohydrate-recognition domains (CRDs) found in many glycan-binding receptors. In most mammalian species, the CD23 residues required to form a sugar-binding site are present, although binding of CD23 to IgE does not involve sugars. Solid-phase binding competition assays, glycoprotein blotting experiments and glycan array analysis employing the lectin-like domains of cow and mouse CD23 demonstrate that they bind to mannose, N-acetylglucosamine, glucose, and fucose and to glycoproteins that bear these sugars in nonreducing terminal positions. Crystal structures of the cow CRD in the presence of α-methyl mannoside and GlcNAcβ1-2Man reveal that a range of oligosaccharide ligands can be accommodated in an open binding site in which most interactions are with a single terminal sugar residue. Although mouse CD23 shows a pattern of monosaccharide and glycoprotein binding similar to cow CD23, the binding is weaker. In contrast, no sugar binding was observed in similar experiments with human CD23. The absence of sugar-binding activity correlates with accumulation of mutations in the CD23 gene in the primate lineage leading to humans, resulting in loss of key sugar-binding residues. These results are consistent with a role for CD23 in many species as a receptor for potentially pathogenic micro-organisms as well as IgE. However, the ability of CD23 to bind several different ligands varies between species, suggesting that it has distinct functions in different organisms.
Taylor ME, Drickamer K, 2019, Mammalian sugar-binding receptors: known functions and unexplored roles, FEBS Journal, Vol: 286, Pages: 1800-1814, ISSN: 1742-464X
Mammalian glycan-binding receptors, sometimes known as lectins, interact withglycans, the oligosaccharide portions ofendogenous mammalian glycoproteins and glycolipids as well as sugars on the surfaces of microbes.Thesereceptors guide glycoproteins out of and back into cells, facilitate communication between cells through both adhesion and signaling, and allow the innate immune system to respond quickly to viral, fungal, bacterial,and parasiticpathogens.For many of the roughly one hundred glycan-binding receptors that are known in humans,there aregood descriptions of what types of glycans they bind and how selectivity for these ligands is achievedat the molecular level.In some cases, there is also comprehensive evidencefor the roles thatthe receptors playat the cellular and organismal levels. In addition to highlighting these well-understood paradigms for glycan-binding receptors, this review will suggest where gaps remain in our understandingof the physiological functions that they can serve.
Taylor M, Snelling T, Smith DF, et al., 2019, Absence of a human ortholog of rodent Kupffer cell galactose-binding receptor encoded by the CLEC4f gene, Glycobiology, Vol: 29, Pages: 332-345, ISSN: 0959-6658
The murine CLEC4f gene encodes the Kupffer cell receptor, a galactose-binding receptor containing a C-type carbohydrate-recognition domain. Orthologs have been identified in nearly 100 species. The receptors from rat and mouse have previously been characterized and data presented here show that functional CLEC4f protein is expressed in domestic cattle (Bos taurus). However, the human CLEC4f gene does not encode a functional receptor because a mutation in the splice acceptor site of the final exon prevents appropriate splicing and a missense mutation disrupts the sugar-binding site. Transcriptomic and PCR analysis of transcripts confirms the absence of a spliced transcript containing the final exon and only background levels of transcripts are detected in human tissues. These mutations are also present in the CLEC4f gene in Neanderthals. In contrast to humans, closely related species, including chimpanzees, do have CLEC4f genes that encode full-length receptors. Affinity chromatography and glycan array results demonstrate that the chimpanzee, bovine and murine proteins all bind to galactose, but they show preferences for different subsets of galactose-containing glycans. In non-human primates, the receptor is expressed in spleen rather than in liver. The results indicate that the CLEC4f protein probably has distinct functions in different species. Absence of the receptor precludes using it for targeting of glycoconjugates to cells in human liver. The fact that CLEC4f protein is expressed in spleen in non-human primates and the close evolutionary relationship of the CLEC4f protein to langerin (CD207) suggest that it may function in the immune system, possibly as a pathogen receptor.
Kim J-W, Budzak J, Liu Y, et al., 2018, Identification of serum glycoprotein ligands for the immunomodulatory receptor blood dendritic cell antigen 2., Glycobiology, Vol: 28, Pages: 592-600
Blood dendritic cell antigen 2 (BDCA-2) is a C-type lectin found on the surface of plasmacytoid dendritic cells. It functions as a glycan-binding receptor that downregulates the production of type I interferons and thus plays a role in oligosaccharide-mediated immunomodulation. The carbohydrate recognition domain in BDCA-2 binds selectively to galactose-terminated bi-antennary glycans. Because the plasmacytoid dendritic cells function in a plasma environment rich in glycoproteins, experiments have been undertaken to identify endogenous ligands for blood dendritic cell antigen 2. A combination of blotting, affinity chromatography and proteomic analysis reveals that serum glycoprotein ligands for BDCA-2 include IgG, IgA and IgM. Compared to binding of IgG, which was previously described, IgA and IgM bind with higher affinity. The association constants for the different subclasses of immunoglobulins are below and roughly proportional to the serum concentrations of these glycoprotein ligands. Binding to the other main serum glycoprotein ligand, α2-macroglobulin, is independent of whether this protease inhibitor is activated. Binding to all of these glycoprotein ligands is mediated predominantly by bi-antennary glycans in which each branch bears a terminal galactose residue. The different affinities of the glycoprotein ligands reflect the different numbers of these galactose-terminated glycans and their degree of exposure on the native glycoproteins. The results suggest that normal serum levels of immunoglobulins could downmodulate interferon stimulation of further antibody production.
Zheng RB, Jégouzo SAF, Joe M, et al., 2017, Insights into Interactions of Mycobacteria with the Host Innate Immune System from a Novel Array of Synthetic Mycobacterial Glycans., ACS Chemical Biology, Vol: 12, Pages: 2990-3002, ISSN: 1554-8929
An array of homogeneous glycans representing all the major carbohydrate structures present in the cell wall of the human pathogen Mycobacterium tuberculosis and other mycobacteria has been probed with a panel of glycan-binding receptors expressed on cells of the mammalian innate immune system. The results provide an overview of interactions between mycobacterial glycans and receptors that mediate uptake and survival in macrophages, dendritic cells, and sinusoidal endothelial cells. A subset of the wide variety of glycan structures present on mycobacterial surfaces interact with cells of the innate immune system through the receptors tested. Endocytic receptors, including the mannose receptor, DC-SIGN, langerin, and DC-SIGNR (L-SIGN), interact predominantly with mannose-containing caps found on the mycobacterial polysaccharide lipoarabinomannan. Some of these receptors also interact with phosphatidyl-myo-inositol mannosides and mannose-containing phenolic glycolipids. Many glycans are ligands for overlapping sets of receptors, suggesting multiple, redundant routes by which mycobacteria can enter cells. Receptors with signaling capability interact with two distinct sets of mycobacterial glycans: targets for dectin-2 overlap with ligands for the mannose-binding endocytic receptors, while mincle binds exclusively to trehalose-containing structures such as trehalose dimycolate. None of the receptors surveyed bind furanose residues, which often form part of the epitopes recognized by antibodies to mycobacteria. Thus, the innate and adaptive immune systems can target different sets of mycobacterial glycans. This array, the first of its kind, represents an important new tool for probing, at a molecular level, biological roles of a broad range of mycobacterial glycans, a task that has not previously been possible.
Feinberg H, Jégouzo SAF, Rex MJ, et al., 2017, Mechanism of pathogen recognition by human dectin-2, Journal of Biological Chemistry, Vol: 292, Pages: 13402-13414, ISSN: 1083-351X
Dectin-2, a C-type lectin on macrophages and other cells of the innate immune system, functions in responses to pathogens, particularly fungi. The carbohydrate-recognition domain (CRD) in dectin-2 is linked to a transmembrane sequence that interacts with the common FcRγ subunit to initiate immune signaling. The molecular mechanism by which dectin-2 selectively binds to pathogens has been investigated by characterizing the CRD expressed in a bacterial system. Competition binding studies indicated that the CRD binds to monosaccharides with modest affinity and that affinity is greatly enhanced for mannose linked α1-2 or α1-4 to a second mannose residue. Glycan array analysis confirmed selective binding of the CRD to glycans that contain Manα1-2Man epitopes. Crystals of the CRD in complex with a mammalian-type high-mannose Man9GlcNAc2 oligosaccharide exhibited interaction with Manα1-2Man on two different termini of the glycan, with the reducing-end mannose residue ligated to Ca2+ in a primary binding site and the nonreducing terminal mannose residue occupying an adjacent secondary site. Comparison of the binding sites in DC-SIGN and langerin, two other pathogen-binding receptors of the innate immune system, revealed why these two binding sites accommodate only terminal Manα1-2Man structures, while dectin-2 can bind Manα1-2Man in internal positions in mannans and other polysaccharides. The specificity and geometry of the dectin-2 binding site provide the molecular mechanism for binding of dectin-2 to fungal mannans and also to bacterial lipopolysaccharides, capsular polysaccharides, and lipoarabinomannans that contain the Manα1-2Man disaccharide unit.
PrabhuDas MR, Baldwin CL, Bollyky PL, et al., 2017, A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease, JOURNAL OF IMMUNOLOGY, Vol: 198, Pages: 3775-3789, ISSN: 0022-1767
Taylor ME, Drickamer K, Schnaar RL, et al., 2017, Discovery and Classification of Glycan-Binding Proteins, Essentials of Glycobiology, Editors: Varki, Publisher: Cold Spring Harbor Laboratory Press, Pages: 361-372, ISBN: 9781621821328
Cummings RD, Schnaar RL, Esko JD, et al., 2017, Principles of Glycan Recognition, Essentials of Glycobiology, Editors: Varki, Publisher: Cold Spring Harbor Laboratory Press, Pages: 373-385, ISBN: 9781621821328
Dos Santos Á, Hadjivasiliou, Ossa F, et al., 2016, Oligomerization domains in the glycan-binding receptors DC-SIGN and DC-SIGNR: sequence variation and stability differences, Protein Science, Vol: 26, Pages: 306-316, ISSN: 1469-896X
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.
Feinberg H, Rambaruth ND, Jégouzo SA, et al., 2016, Binding sites for acylated trehalose analogs of glycolipid ligands on an extended carbohydrate-recognition domain of the macrophage receptor mincle, Journal of Biological Chemistry, Vol: 291, Pages: 21222-21233, ISSN: 1083-351X
The macrophage receptor mincle binds to trehalose dimycolate on the surface of Mycobacterium tuberculosis. Signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. In previous work, the mechanism for binding of the sugar headgroup of trehalose dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are attached to the 6-hydroxyl groups, has been the subject of speculation. In the work reported here, the interaction of trehalose derivatives with bovine mincle has been probed with a series of synthetic mimics of trehalose dimycolate in binding assays, in structural studies by x-ray crystallography, and by site-directed mutagenesis. Binding studies reveal that, rather than reflecting specific structural preference, the apparent affinity of mincle for ligands with hydrophobic substituents correlates with their overall size. Structural and mutagenesis analysis provides evidence for interaction of the hydrophobic substituents with multiple different portions of the surface of mincle and confirms the presence of three Ca2+-binding sites. The structure of an extended portion of the extracellular domain of mincle, beyond the minimal C-type carbohydrate-recognition domain, also constrains the way that the binding domains may interact on the surface of macrophages.
Breiman A, Robles MDL, Trecesson SDC, et al., 2016, Carcinoma-associated fucosylated antigens are markers of the epithelial state and can contribute to cell adhesion through CLEC17A (Prolectin), Oncotarget, Vol: 7, Pages: 14064-14082, ISSN: 1949-2553
Taylor ME, Drickamer K, 2015, Recent insights into structures and functions of C-type lectins in the immune system, Current Opinion in Structural Biology, Vol: 34, Pages: 26-34, ISSN: 0959-440X
The majority of the C-type lectin-like domains in the human genome likely to bind sugars have been investigated structurally, although novel mechanisms of sugar binding are still being discovered. In the immune system, adhesion and endocytic receptors that bind endogenous mammalian glycans are often conserved, while pathogen-binding C-type lectins on cells of the innate immune system are more divergent. Lack of orthology between some human and mouse receptors, as well as overlapping specificities of many receptors and formation of receptor hetero-oligomers, can make it difficult to define the roles of individual receptors. There is good evidence that C-type lectins initiate signalling pathways in several different ways, but this function remains the least well understood from a mechanistic perspective.
Drickamer K, Jégouzo SAF, Feinberg H, et al., 2015, A Novel Mechanism for Binding of Galactose-terminatedGlycans by the C-type Carbohydrate Recognition Domain inBlood Dendritic Cell Antigen 2, Journal of Biological Chemistry, Vol: 290, Pages: 16759-16771, ISSN: 1083-351X
Rambaruth ND, Jégouzo SA, Marlor H, et al., 2015, Mouse mincle: characterization as a model for human mincle and evolutionary implications., Molecules, Vol: 20, Pages: 6670-6682, ISSN: 1420-3049
Mincle, the macrophage-inducible C-type lectin also known as CLEC-4E, binds to the mycobacterial glycolipid trehalose dimycolate and initiates a signaling cascade by serving as a receptor for Mycobacterium tuberculosis and other pathogenic mycobacterial species. Studies of the biological functions of human mincle often rely on mouse models, based on the assumption that the biological properties of the mouse receptor mimic those of the human protein. Experimental support for this assumption has been obtained by expression of the carbohydrate-recognition domain of mouse mincle and characterization of its interaction with small molecule analogs of trehalose dimycolate. The results confirm that the ligand-binding properties of mouse mincle closely parallel those of the human receptor. These findings are consistent with the conservation of key amino acid residues that have been shown to form the ligand-binding site in human and cow mincle. Sequence alignment reveals that these residues are conserved in a wide range of mammalian species, suggesting that mincle has a conserved function in binding ligands that may include endogenous mammalian glycans or pathogen glycans in addition to trehalose dimycolate.
Jacobsen KM, Keiding UB, Clement LL, et al., 2015, The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle, MEDCHEMCOMM, Vol: 6, Pages: 647-652, ISSN: 2040-2503
Taylor ME, Drickamer K, 2015, C-Type Lectin Family: Overview, Glycoscience: Biology and Medicine, Pages: 1015-1020, ISBN: 9784431548409
© Springer Japan 2015. Members of the C-type lectin family of glycan-binding receptors in animals contain modular carbohydrate recognition domains (CRDs) that form a subset of a larger structural class of protein modules designated C-type lectin-like domains. Two broad categories of C-type CRDs bind either mannose and related sugars or galactose and related sugars at the Ca2+-binding site. Small changes in sequence have resulted in switches in this primary specificity. Additional selectivity for more complex glycans results from secondary binding interactions. In mammals, C-type CRDs recognize either endogenous glycans or sugars on potentially pathogenic microorganisms. Recognition of endogenous sugar tags on cell surfaces can initiate cell adhesion and signaling, while binding to sugars on serumglycoproteins can initiate clearance from serum. C-type CRDs that bind to sugars on the surfaces of pathogens form part of the innate immune system.
Jegouzo SAF, Harding EC, Acton O, et al., 2014, Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate, GLYCOBIOLOGY, Vol: 24, Pages: 1291-1300, ISSN: 0959-6658
Drickamer K, Taylor ME, 2014, Convergent and divergent mechanisms of sugar recognition across kingdoms, Current Opinion in Structural Biology, Vol: 28, Pages: 14-22, ISSN: 0959-440X
Protein modules that bind specific oligosaccharides are found across all kingdoms of life from single-celled organisms to man. Different, overlapping and evolving designations for sugar-binding domains in proteins can sometimes obscure common features that often reflect convergent solutions to the problem of distinguishing sugars with closely similar structures and binding them with sufficient affinity to achieve biologically meaningful results. Structural and functional analysis has revealed striking parallels between protein domains with widely different structures and evolutionary histories that employ common solutions to the sugar recognition problem. Recent studies also demonstrate that domains descended from common ancestors through divergent evolution appear more widely across the kingdoms of life than had previously been recognized.
Feinberg H, Rowntree TJW, Tan SLW, et al., 2013, Common Polymorphisms in Human Langerin Change Specificity for Glycan Ligands, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 36762-36771
Feinberg H, Jegouzo SAF, Rowntree TJW, et al., 2013, Mechanism for Recognition of an Unusual Mycobacterial Glycolipid by the Macrophage Receptor Mincle, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 28457-28465
Jegouzo SAF, Quintero-Martinez A, Ouyang X, et al., 2013, Organization of the extracellular portion of the macrophage galactose receptor: A trimeric cluster of simple binding sites for N-acetylgalactosamine, GLYCOBIOLOGY, Vol: 23, Pages: 853-864, ISSN: 0959-6658
Leckband DE, Menon S, Rosenberg K, et al., 2011, Geometry and Adhesion of Extracellular Domains of DC-SIGNR Neck Length Variants Analyzed by Force-Distance Measurements, BIOCHEMISTRY, Vol: 50, Pages: 6125-6132, ISSN: 0006-2960
Graham SA, Antonopoulos A, Hitchen PG, et al., 2011, Identification of Neutrophil Granule Glycoproteins as Lewis(x)-containing Ligands Cleared by the Scavenger Receptor C-type Lectin, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 24336-24349
Pipirou Z, Powlesland AS, Steffen I, et al., 2011, Mouse LSECtin as a model for a human Ebola virus receptor, GLYCOBIOLOGY, Vol: 21, Pages: 806-812, ISSN: 0959-6658
Powlesland AS, Marcela Barrio M, Mordoh J, et al., 2011, Glycoproteomic characterization of carriers of the CD15/Lewis(x) epitope on Hodgkin's Reed-Sternberg cells, BMC BIOCHEMISTRY, Vol: 12, ISSN: 1471-2091
Feinberg H, Taylor ME, Razi N, et al., 2011, Structural Basis for Langerin Recognition of Diverse Pathogen and Mammalian Glycans through a Single Binding Site, JOURNAL OF MOLECULAR BIOLOGY, Vol: 405, Pages: 1027-1039, ISSN: 0022-2836
Taylor ME, Drickamer K, 2011, Introduction to Glycobiology, Third Edition, Publisher: Oxford University Press, ISBN: 978-0-19-956911-3
Coombs PJ, Harrison R, Pemberton S, et al., 2010, Identification of Novel Contributions to High-affinity Glycoprotein-Receptor Interactions using Engineered Ligands, JOURNAL OF MOLECULAR BIOLOGY, Vol: 396, Pages: 685-696, ISSN: 0022-2836
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.