title: 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.affiliation: Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain.
authors.forename: Carlo
authors.initials: C
authors.lastname: Manzo
authors.forename: Juan A
authors.initials: JA
authors.lastname: Torreno-Pina
authors.forename: Ben
authors.initials: B
authors.lastname: Joosten
authors.forename: Inge
authors.initials: I
authors.lastname: Reinieren-Beeren
authors.forename: Emilio J
authors.initials: EJ
authors.lastname: Gualda
authors.forename: Pablo
authors.initials: P
authors.lastname: Loza-Alvarez
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Maria F
authors.initials: MF
authors.lastname: Garcia-Parajo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cambi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D001665:Binding Sites; D001703:Biophysics / Q000379:methods; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004058:Diffusion; D006801:Humans; D037102:Lectins / Q000737:chemistry*; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013499:Surface Properties; D013997:Time Factors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D002966:Clathrin; D037102:Lectins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin