Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR

Both the dendritic cell receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR bind human immunodeficiency virus and enhance infection. However, biochemical and structural comparison of these receptors now reveals that they have very different physiological functions. By screening an extensive glycan array, we demonstrated that DC-SIGN and DC-SIGNR have distinct ligand-binding properties. Our structural and mutagenesis data explain how both receptors bind high-mannose oligosaccharides on enveloped viruses and why only DC-SIGN binds blood group antigens, including those present on microorganisms. DC-SIGN mediates endocytosis, trafficking as a recycling receptor and releasing ligand at endosomal pH, whereas DC-SIGNR does not release ligand at low pH or mediate endocytosis. Thus, whereas DC-SIGN has dual ligand-binding properties and functions both in adhesion and in endocytosis of pathogens, DC-SIGNR binds a restricted set of ligands and has only the properties of an adhesion receptor.

[1]  C. Figdor,et al.  Identification of DC-SIGN, a Novel Dendritic Cell–Specific ICAM-3 Receptor that Supports Primary Immune Responses , 2000, Cell.

[2]  T. Geijtenbeek,et al.  Cutting Edge: Carbohydrate Profiling Identifies New Pathogens That Interact with Dendritic Cell-Specific ICAM-3-Grabbing Nonintegrin on Dendritic Cells , 2003, The Journal of Immunology.

[3]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[4]  K. Drickamer.  C-type lectin-like domains. , 1999, Current opinion in structural biology.

[5]  W. Weis,et al.  Structural Basis for Selective Recognition of Oligosaccharides by DC-SIGN and DC-SIGNR , 2001, Science.

[6]  M. Monsigny,et al.  Oligolysine-based Oligosaccharide Clusters , 2003, Journal of Biological Chemistry.

[7]  R. Doms,et al.  DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. , 2003, Virology.

[8]  R. Doms,et al.  DC-SIGN and DC-SIGNR: helping hands for HIV. , 2001, Trends in immunology.

[9]  Maureen E. Taylor,et al.  Glycan arrays for functional glycomics , 2002, Genome Biology.

[10]  James C. Paulson,et al.  Sialoside Specificity of the Siglec Family Assessed Using Novel Multivalent Probes , 2003, Journal of Biological Chemistry.

[11]  R. Steinman.  DC-SIGN A Guide to Some Mysteries of Dendritic Cells , 2000, Cell.

[12]  R. Cummings,et al.  Binding of Glycosulfopeptides to P-selectin Requires Stereospecific Contributions of Individual Tyrosine Sulfate and Sugar Residues* , 2000, The Journal of Biological Chemistry.

[13]  Daniel A. Mitchell,et al.  A Novel Mechanism of Carbohydrate Recognition by the C-type Lectins DC-SIGN and DC-SIGNR , 2001, The Journal of Biological Chemistry.

[14]  K. Drickamer,et al.  Endocytosis of N-acetylglucosamine-containing glycoproteins by rat fibroblasts expressing a single species of chicken liver glycoprotein receptor. , 1988, The Journal of biological chemistry.

[15]  K. Drickamer,et al.  Identification of Amino Acid Residues That Determine pH Dependence of Ligand Binding to the Asialoglycoprotein Receptor during Endocytosis* , 1999, The Journal of Biological Chemistry.

[16]  Liang Tong,et al.  Combined molecular replacement , 1996 .

[17]  William I. Weis,et al.  Structural Analysis of Monosaccharide Recognition by Rat Liver Mannose-binding Protein (*) , 1996, The Journal of Biological Chemistry.

[18]  Maureen E. Taylor,et al.  Characterization of carbohydrate recognition by langerin, a C-type lectin of Langerhans cells. , 2003, Glycobiology.

[19]  E. Soilleux.  DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin) and DC-SIGN-related (DC-SIGNR): friend or foe? , 2003, Clinical science.

[20]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[21]  Alessandra Cambi,et al.  Dual function of C-type lectin-like receptors in the immune system. , 2003, Current opinion in cell biology.

[22]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[23]  Á. Corbí,et al.  C-Type Lectins DC-SIGN and L-SIGN Mediate Cellular Entry by Ebola Virus in cis and in trans , 2002, Journal of Virology.

[24]  Collaborative Computational,et al.  The CCP4 suite: programs for protein crystallography. , 1994, Acta crystallographica. Section D, Biological crystallography.

[25]  Y. Kooyk,et al.  DC-SIGN: escape mechanism for pathogens , 2003, Nature Reviews Immunology.

[26]  Antonio Lanzavecchia,et al.  The Dendritic Cell-Specific Adhesion Receptor DC-SIGN Internalizes Antigen for Presentation to T Cells1 , 2002, The Journal of Immunology.

[27]  Jorge Navaza,et al.  [33] AMoRe: An automated molecular replacement program package. , 1997, Methods in enzymology.

[28]  W. Weis,et al.  The C‐type lectin superfamily in the immune system , 1998, Immunological reviews.

[29]  E. Harlow,et al.  Antibodies: A Laboratory Manual , 1988 .

[30]  Alessandra Cambi,et al.  The C‐type lectin DC‐SIGN (CD209) is an antigen‐uptake receptor for Candida albicans on dendritic cells , 2003, European journal of immunology.

[31]  T. Geijtenbeek,et al.  A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance. , 2003, Trends in molecular medicine.