Binding-site geometry and flexibility in DC-SIGN demonstrated with surface force measurements

Area of Science:

• Immunology
• Structural Biology
• Biophysics

Background:

• Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) is a C-type lectin receptor on dendritic cells.
• DC-SIGN recognizes conserved carbohydrate structures on pathogens, including HIV, playing a role in innate immunity.
• The precise arrangement of DC-SIGN's carbohydrate-binding sites and their role in pathogen recognition are not fully understood.

Purpose of the Study:

• To investigate the conformational state of the DC-SIGN extracellular domain.
• To understand how glycan binding influences the receptor's structure and function.
• To elucidate the role of ligand mobility in DC-SIGN mediated pathogen recognition.

Main Methods:

• Surface force measurements using apposing lipid bilayers.
• Incorporation of the extracellular domain of DC-SIGN into one bilayer.
• Display of neoglycolipids with specific oligosaccharide ligands on the opposing bilayer.

Main Results:

• DC-SIGN adopts an extended conformation in the absence of ligands.
• Glycan binding induces a conformational change, repositioning carbohydrate-recognition domains.
• Lateral mobility of membrane-bound ligands enhances multivalent binding to the DC-SIGN oligomer.
• DC-SIGN's flexible binding mechanism differs from receptors with fixed-site spacing.

Conclusions:

• The extended conformation and ligand-induced conformational changes are crucial for DC-SIGN's pathogen recognition.
• Membrane-bound ligand mobility facilitates efficient multivalent interactions, enhancing pathogen targeting.
• DC-SIGN utilizes a dynamic binding strategy distinct from other lectin receptors.