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

Abstract

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.

Compact, Polyvalent Mannose Quantum Dots as Sensitive, Ratiometric FRET Probes for Multivalent Protein–Ligand Interactions

“…Moreover, the FRET signal was effectively inhibited by free mannose in a dose‐dependent manner, while galactose was much less effective at inhibiting this binding (Figure S5). This result agrees well with DC‐SIGN's binding specificity for mannose over galactose 11. A higher mannose concentration ( K I ) was required to inhibit DC‐SIGN binding to QD‐EG 3 ‐Man than to QD‐PEG 13 ‐Man (1.4 vs. 0.80 m m , see Table 1), which was consistent with the former binding being tighter (apparent K D 0.32 vs. 0.6 μ m ).…”

“…The different CRD arrangement and accessibility in DC‐SIGN/R may account for their distinct viral binding/transmission properties. It also correlates well with the biological roles: the high accessibility of DC‐SIGN should enable rapid antigen capture to trigger the immune response as required for an antigen‐presenting dendritic cell surface endocytic receptor 11, 14. Whereas the endothelial cell surface adhesion receptor DC‐SIGNR11 may only recognize specific, spatial and orientation‐matched multivalent glycans.…”

“…The observed FRET signal was completely diminished in the absence of Ca 2+ (Figure S4), suggesting the signal was indeed the result of Ca 2+ ‐dependent DC‐SIGN‐mannose binding 11. Moreover, the FRET signal was effectively inhibited by free mannose in a dose‐dependent manner, while galactose was much less effective at inhibiting this binding (Figure S5).…”

Expression of dendritic cell lysosome-associated membrane protein and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin in condyloma acuminatum lesions

“…12 The physiological functions of DC-SIGN include two aspects: recognition of pathogens by receptors and cell adhesion. 16 DC-SIGN on the surfaces of peripheral immature DCs can interact with ICAM-2, which is highly expressed in the vascular and lymphatic endothelium, in order to facilitate these DCs to enter lymph nodes and other immune organs. 17 Thus, antigens can be captured, engulfed and then processed by DCs into MHC-antigen complexes in the lysosomes, which are presented to T cells.…”

Glycoconjugates and Glycomimetics as Microbial Anti-Adhesives

“…The glycans interact primarily with a Ca 2+ ion exposed at the surface of DC-SIGN carbohydrate recognition domain (CRD). X-ray data are available for complexes of DC-SIGN CRD with mannose oligosaccharides, and with the fucosylated oligosaccharide Lewis X [40][41][42][43]. blocking viral adhesion and entry in sexually transmitted HIV infection.…”