title: Glycosaminoglycans are interactants of Langerin: comparison with gp120 highlights an unexpected calcium-independent binding mode.
abstract: Langerin is a C-type lectin specifically expressed in Langerhans cells. As recently shown for HIV, Langerin is thought to capture pathogens and mediate their internalisation into Birbeck Granules for elimination. However, the precise functions of Langerin remain elusive, mostly because of the lack of information on its binding properties and physiological ligands. Based on recent reports that Langerin binds to sulfated sugars, we conducted here a comparative analysis of Langerin interaction with mannose-rich HIV glycoprotein gp120 and glycosaminoglycan (GAGs), a family of sulfated polysaccharides expressed at the surface of most mammalian cells. Our results first revealed that Langerin bound to these different glycans through very distinct mechanisms and led to the identification of a novel, GAG-specific binding mode within Langerin. In contrast to the canonical lectin domain, this new binding site showed no Ca(2+)-dependency, and could only be detected in entire, trimeric extracellular domains of Langerin. Interestingly binding to GAGs, did not simply rely on a net charge effect, but rather on more discrete saccharide features, such as 6-O-sulfation, or iduronic acid content. Using molecular modelling simulations, we proposed a model of Langerin/heparin complex, which located the GAG binding site at the interface of two of the three Carbohydrate-recognition domains of the protein, at the edge of the a-helix coiled-coil. To our knowledge, the binding properties that we have highlighted here for Langerin, have never been reported for C-type lectins before. These findings provide new insights towards the understanding of Langerin biological functions.
authors.affiliation: Groupe Membrane & Pathogens, Institut de Biologie Structurale, Université Joseph Fourier, Grenoble, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chabrol
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.forename: Antoine
authors.initials: A
authors.lastname: Daina
authors.forename: Emilie
authors.initials: E
authors.lastname: Vassal-Stermann
authors.forename: Michel
authors.initials: M
authors.lastname: Thepaut
authors.forename: Eric
authors.initials: E
authors.lastname: Girard
authors.forename: Romain R
authors.initials: RR
authors.lastname: Vivès
authors.forename: Franck
authors.initials: F
authors.lastname: Fieschi
mesh_terms: D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D000078404:Epidermal Cells; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D007801:Langerhans Cells / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry* / Q000378:metabolism*; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009092:Mucous Membrane / Q000166:cytology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012984:Software
chemical_list: D015703:Antigens, CD; C121916:CD207 protein, human; D006025:Glycosaminoglycans; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; C514793:gp120 protein, Human immunodeficiency virus 1; D006493:Heparin; D002118:Calcium