title: Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R.
abstract: IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses. It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common γ-chain. A hallmark of the class I cytokine receptors is the class I cytokine receptor signature motif (WSXWS). The exact role of this motif has not been determined yet; however, it has been implicated in diverse functions, including ligand binding, receptor internalization, proper folding, and export, as well as signal transduction. Furthermore, the WXXW motif is known to be a consensus sequence for C-mannosylation. Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. We furthermore demonstrate that a sugar chain bridges the two fibronectin domains that constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including mannosylation. The glycan thus transforms the V-shaped receptor into an A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
authors.forename: Ole J
authors.initials: OJ
authors.lastname: Hamming
authors.forename: Lishan
authors.initials: L
authors.lastname: Kang
authors.forename: Anders
authors.initials: A
authors.lastname: Svensson
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Karlsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Rahbek-Nielsen
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: Siv A
authors.initials: SA
authors.lastname: Hjorth
authors.forename: Kent
authors.initials: K
authors.lastname: Bondensgaard
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006031:Glycosylation; D006801:Humans; D007378:Interleukins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D053655:Receptors, Interleukin-21 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21; D008358:Mannose