The neck region of the C-type lectin DC-SIGN regulates its surface spatiotemporal organization and virus-binding capacity on antigen-presenting cells.

Abstract

The C-type lectin DC-SIGN expressed on dendritic cells (DCs) facilitates capture and internalization of a plethora of different pathogens. Although it is known that DC-SIGN organizes in nanoclusters at the surface of DCs, the molecular mechanisms responsible for this well defined nanopatterning and role in viral binding remain enigmatic. By combining biochemical and advanced biophysical techniques, including optical superresolution and single particle tracking, we demonstrate that DC-SIGN intrinsic nanoclustering strictly depends on its molecular structure. DC-SIGN nanoclusters exhibited free, Brownian diffusion on the cell membrane. Truncation of the extracellular neck region, known to abrogate tetramerization, significantly reduced nanoclustering and concomitantly increased lateral diffusion. Importantly, DC-SIGN nanocluster dissolution exclusively compromised binding to nanoscale size pathogens. Monte Carlo simulations revealed that heterogeneity on nanocluster density and spatial distribution confers broader binding capabilities to DC-SIGN. As such, our results underscore a direct relationship between spatial nanopatterning, driven by intermolecular interactions between the neck regions, and receptor diffusion to provide DC-SIGN with the exquisite ability to dock pathogens at the virus length scale. Insight into how virus receptors are organized prior to virus binding and how they assemble into functional platforms for virus docking is helpful to develop novel strategies to prevent virus entry and infection.

• Authors: Carlo Manzo, Juan A Torreno-Pina, Ben Joosten, Inge Reinieren-Beeren, Emilio J Gualda, Pablo Loza-Alvarez, Carl G Figdor, Maria F Garcia-Parajo, Alessandra Cambi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 46 Pg. 38946-55 (Nov 09 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 23019323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Clathrin
• DC-specific ICAM-3 grabbing nonintegrin
• Lectins
• Lectins, C-Type
• Receptors, Cell Surface

Topics

• Animals
• Antigen-Presenting Cells (metabolism)
• Binding Sites
• Biophysics (methods)
• CHO Cells
• Cell Adhesion Molecules (metabolism)
• Cell Membrane (metabolism)
• Clathrin (metabolism)
• Cricetinae
• Cricetulus
• Cytoplasm (metabolism)
• Dendritic Cells (cytology)
• Diffusion
• Humans
• Lectins (chemistry)
• Lectins, C-Type (metabolism)
• Mice
• Models, Biological
• NIH 3T3 Cells
• Protein Binding
• Receptors, Cell Surface (metabolism)
• Surface Properties
• Time Factors