Dual specificity of Langerin to sulfated and mannosylated glycans via a single C-type carbohydrate recognition domain.
Langerin is categorized as a C-type lectin selectively expressed in Langerhans cells, playing roles in the first line of defense against pathogens and in Birbeck granule formation. Although these functions are thought to be exerted through glycan-binding activity of the C-type carbohydrate recognition domain, sugar-binding properties of Langerin have not been fully elucidated in relation to its biological functions. Here, we investigated the glycan-binding specificity of Langerin using comprehensive glycoconjugate microarray, quantitative frontal affinity chromatography, and conventional cell biological analyses. Langerin showed outstanding affinity to galactose-6-sulfated oligosaccharides, including keratan sulfate, while it preserved binding activity to mannose, as a common feature of the C-type lectins with an EPN motif. By a mutagenesis study, Lys-299 and Lys-313 were found to form extended binding sites for sulfated glycans. Consistent with the former observation, the sulfated Langerin ligands were found to be expressed in brain and spleen, where the transcript of keratan sulfate 6-O-sulfotransferase is expressed. Moreover, such sulfated ligands were up-regulated in glioblastoma relative to normal brain tissues, and Langerin-expressing cells were localized in malignant brain tissues. Langerin also recognized pathogenic fungi, such as Candida and Malassezia, expressing heavily mannosylated glycans. These observations provide strong evidence that Langerin mediates diverse functions on Langerhans cells through dual recognition of sulfated as well as mannosylated glycans by its uniquely evolved C-type carbohydrate-recognition domain.
Tateno
Hiroaki
H
Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Central 2, 1-1-1 Umezono, Ibaraki 305-8568, Japan.
Ohnishi
Koji
K
Yabe
Rikio
R
Hayatsu
Norihito
N
Sato
Takashi
T
Takeya
Motohiro
M
Narimatsu
Hisashi
H
Hirabayashi
Jun
J
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001932:Brain Neoplasms / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005658:Fungi / Q000378:metabolism; D005909:Glioblastoma / Q000737:chemistry; D006801:Humans; D007801:Langerhans Cells; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008358:Mannose; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D040081:Protein Array Analysis; D011485:Protein Binding; D013431:Sulfates
D015703:Antigens, CD; C121916:CD207 protein, human; D037181:Lectins, C-Type; D008024:Ligands; D037241:Mannose-Binding Lectins; D011134:Polysaccharides; D013431:Sulfates; D008358:Mannose