Contribution to ligand binding by multiple carbohydrate-recognition domains in the macrophage mannose receptor.

Abstract ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura. The formation of autoantibodies depends on the activation of CD4+ T cells. This process requires immune recognition, endocytosis, and subsequent processing of ADAMTS13 into peptides that are presented on MHC class II molecules to CD4+ T cells by dendritic cells (DCs). In the present study, we investigated endocytosis of recombinant ADAMTS13 by immature monocyte-derived DCs using flow cytometry and confocal microscopy. After incubation of fluorescently labeled ADAMTS13 with DCs, significant uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked by the addition of EGTA and mannan. ADAMTS13 endocytosis was decreased in the presence of a blocking mAb directed toward the macrophage mannose receptor (MR). Furthermore, siRNA silencing of MR reduced the uptake of ADAMTS13 by DCs. In addition, in vitro binding studies confirmed the interaction of ADAMTS13 with the carbohydrate recognition domains of MR. The results of the present study indicate that sugar moieties on ADAMTS13 interact with MR, thereby promoting its endocytosis by APCs.

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Characterization of the murine macrophage mannose receptor: demonstration that the downregulation of receptor expression mediated by interferon-gamma occurs at the level of transcription

Blood ◽

10.1182/blood.v80.9.2363.2363 ◽

1992 ◽

Vol 80 (9) ◽

pp. 2363-2373 ◽

Cited By ~ 2

Author(s):

N Harris ◽

M Super ◽

M Rits ◽

G Chang ◽

RA Ezekowitz

Keyword(s):

Amino Acid ◽

Cell Surface ◽

Interferon Gamma ◽

Mannose Receptor ◽

Receptor Expression ◽

Ifn Gamma ◽

Reading Frame ◽

Transmembrane Glycoprotein ◽

Macrophage Mannose Receptor ◽

Carbohydrate Recognition Domains

Abstract The macrophage mannose receptor (MMR) is a 175-Kd cell-surface transmembrane glycoprotein that is expressed on tissue macrophages where it functions both to mediate the uptake of mannose-rich glycoproteins and as a phagocytic receptor for bacteria, yeasts, and other pathogenic microorganisms. In this report we describe the cloning of the full-length cDNA of the mouse macrophage mannose receptor and we investigate the level at which interferon gamma (IFN-gamma) downregulates mannose receptor expression. The latter is a marker of the functional state of the cell as high levels are expressed on resident and inflammatory macrophages, whereas cells activated by treatment with IFN-gamma have decreased-to-absent cell-surface mannose receptor expression. The murine MMR cDNA contains an open reading frame that predicts a protein of 1,456 amino acids. Transient expression of the protein in heterologous cells shows that this cDNA encodes a functional mannose receptor. The deduced amino acid sequence of this protein has an overall 82% homology with the human mannose receptor and as such, the ectodomain contains an N-terminus that is cysteine-rich followed by a fibronectin type II domain and eight carbohydrate recognition domains (CRDs). The ectodomain is linked to a hydrophobic transmembrane region and a 46-amino acid cytoplasmic tail. All of the eight CRDs are particularly well conserved, especially CRD4, which shows 92% homology with the equivalent region of the human protein. Steady-state levels of murine MMR mRNA were measured in the macrophage cell line J774E, which is known to express the protein at the cell surface. These levels were decreased by a 4- to 8-hour incubation with IFN-gamma, but were almost abolished by overnight treatment with this cytokine. Nuclear run-on experiments showed that IFN-gamma inhibits MMR gene transcription. Therefore, the regulation of mannose receptor expression by IFN-gamma provides a novel system in which to study the mechanisms by which this cytokine represses gene expression.

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Structure of a C-type Carbohydrate Recognition Domain from the Macrophage Mannose Receptor

Journal of Biological Chemistry ◽

10.1074/jbc.m002366200 ◽

2000 ◽

Vol 275 (28) ◽

pp. 21539-21548 ◽

Cited By ~ 80

Author(s):

Hadar Feinberg ◽

Shaun Park-Snyder ◽

Anand R. Kolatkar ◽

Charles T. Heise ◽

Maureen E. Taylor ◽

...

Keyword(s):

Mannose Receptor ◽

Carbohydrate Recognition Domain ◽

Carbohydrate Recognition ◽

Macrophage Mannose Receptor

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Endogenous ligands of carbohydrate recognition domains of the mannose receptor in murine macrophages, endothelial cells and secretory cells; potential relevance to inflammation and immunity

European Journal of Immunology ◽

10.1002/1521-4141(200106)31:6<1857::aid-immu1857>3.0.co;2-d ◽

2001 ◽

Vol 31 (6) ◽

pp. 1857-1866 ◽

Cited By ~ 51

Author(s):

Sheena A. Linehan ◽

Luisa Martínez-Pomares ◽

Rosângela P. da Silva ◽

Siamon Gordon

Keyword(s):

Endothelial Cells ◽

Mannose Receptor ◽

Secretory Cells ◽

Carbohydrate Recognition ◽

Endogenous Ligands ◽

Murine Macrophages ◽

Carbohydrate Recognition Domains

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Orientation of sugars bound to the principal C-type carbohydrate-recognition domain of the macrophage mannose receptor

Biochemical Journal ◽

10.1042/bj3330601 ◽

1998 ◽

Vol 333 (3) ◽

pp. 601-608 ◽

Cited By ~ 23

Author(s):

Paul G. HITCHEN ◽

Nicholas P. MULLIN ◽

Maureen E. TAYLOR

Keyword(s):

Binding Site ◽

Rat Liver ◽

Binding Protein ◽

Mannose Receptor ◽

Tyrosine Residue ◽

Carbohydrate Recognition ◽

Sugar Binding ◽

Macrophage Mannose Receptor ◽

Mannose Binding Protein ◽

Mannose Binding

The extracellular region of the macrophage mannose receptor, a protein involved in the innate immune response, contains eight C-type carbohydrate-recognition domains (CRDs). The fourth of these domains, CRD-4, is central to ligand binding by the receptor, and binds mannose, fucose and N-acetylglucosamine by direct ligation to Ca2+. Site-directed mutagenesis combined with NMR and molecular modelling have been used to determine the orientation of monosaccharides bound to CRD-4. Two resonances in the 1H NMR spectrum of CRD-4 that are perturbed on sugar binding are identified as a methyl proton from a leucine side chain in the core of the domain and the H-2 proton of a histidine close to the predicted sugar-binding site. The effects of mutagenesis of this histidine residue, a nearby isoleucine residue and a tyrosine residue previously shown to stack against sugars bound to CRD-4 show the absolute orientation of sugars in the binding site. N-Acetylglucosamine binds to CRD-4 of the mannose receptor in the orientation seen in crystal structures of the CRD of rat liver mannose-binding protein. Mannose binds to CRD-4 in the orientation seen in the CRD of rat serum mannose-binding protein and is rotated by 180 ° relative to GlcNAc bound to CRD-4. Interaction of the O-methyl group and C-1 of α-methyl Fuc with the tyrosine residue accounts for the strong preference of CRD-4 for this anomer of fucose. Both anomers of fucose bind to CRD-4 in the orientation seen in rat liver mannose-binding protein.

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Endo180, an endocytic recycling glycoprotein related to the macrophage mannose receptor is expressed on fibroblasts, endothelial cells and macrophages and functions as a lectin receptor

Journal of Cell Science ◽

10.1242/jcs.113.6.1021 ◽

2000 ◽

Vol 113 (6) ◽

pp. 1021-1032 ◽

Cited By ~ 3

Author(s):

H. Sheikh ◽

H. Yarwood ◽

A. Ashworth ◽

C.M. Isacke

Keyword(s):

Endothelial Cells ◽

Mannose Receptor ◽

Carbohydrate Recognition ◽

Lectin Receptor ◽

Extracellular Milieu ◽

Morphological Studies ◽

Macrophage Mannose Receptor ◽

Polypeptide Backbone

Endo180 was previously characterized as a novel, cell type specific, recycling transmembrane glycoprotein. This manuscript describes the isolation of a full length human Endo180 cDNA clone which was shown to encode a fourth member of a family of proteins comprising the macrophage mannose receptor, the phospholipase A(2) receptor and the DEC-205/MR6 receptor. This receptor family is unusual in that they contain 8–10 C-type lectin carbohydrate recognition domains in a single polypeptide backbone, however, only the macrophage mannose receptor had been shown to function as a lectin. Sequence analysis of Endo180 reveals that the second carbohydrate recognition domain has retained key conserved amino acids found in other functional C-type lectins. Furthermore, it is demonstrated that this protein displays Ca(2+)-dependent binding to N-acetylglucosamine but not mannose affinity columns. In order to characterize the physiological function of Endo180, a series of biochemical and morphological studies were undertaken. Endo180 is found to be predominantly expressed in vivo and in vitro on fibroblasts, endothelial cells and macrophages, and the distribution and post-translational processing in these cells is consistent with Endo180 functioning to internalize glycosylated ligands from the extracellular milieu for release in an endosomal compartment.

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Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)38325-5 ◽

1990 ◽

Vol 265 (21) ◽

pp. 12156-12162 ◽

Cited By ~ 4

Author(s):

M E Taylor ◽

J T Conary ◽

M R Lennartz ◽

P D Stahl ◽

K Drickamer

Keyword(s):

Primary Structure ◽

Mannose Receptor ◽

Carbohydrate Recognition ◽

Carbohydrate Recognition Domains

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Mechanism of Ca2+and Monosaccharide Binding to a C-type Carbohydrate-recognition Domain of the Macrophage Mannose Receptor

Journal of Biological Chemistry ◽

10.1074/jbc.272.9.5668 ◽

1997 ◽

Vol 272 (9) ◽

pp. 5668-5681 ◽

Cited By ~ 64

Author(s):

Nicholas P. Mullin ◽

Paul G. Hitchen ◽

Maureen E. Taylor

Keyword(s):

Mannose Receptor ◽

Carbohydrate Recognition Domain ◽

Carbohydrate Recognition ◽

Macrophage Mannose Receptor

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Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1785 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1785-1794 ◽

Cited By ~ 339

Author(s):

R A Ezekowitz ◽

K Sastry ◽

P Bailly ◽

A Warner

Keyword(s):

Cytoplasmic Tail ◽

Mannose Receptor ◽

Integral Membrane Protein ◽

Human Macrophage ◽

Carbohydrate Recognition ◽

Macrophage Mannose Receptor ◽

Receptor Cdna ◽

I Cells ◽

Fibronectin Type

The macrophage mannose receptor is an integral membrane protein expressed on the surface of tissue macrophages. After ligation of mannose-rich glycoconjugates or pathogens, the receptor mediates endocytosis and phagocytosis of the bound ligands by macrophages. The cDNA-derived primary structure of the mannose receptor predicts a cysteine-rich NH2-terminal domain, followed by a fibronectin type II region. The remainder of the ectodomain is comprised of eight carbohydrate recognition-like domains, followed by a transmembrane region, and a cytoplasmic tail. Transfection of the mannose receptor cDNA into Cos-I cells is necessary for receptor-mediated endocytosis of mannose-rich glycoconjugate as well as phagocytosis of yeasts. Deletion of the cytoplasmic tail results in a mutant receptor that is able to bind but not ingest the ligated pathogens, suggesting that the signal for phagocytosis is contained in the cytoplasmic tail.

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