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Interleukin (IL) 21 is a class I cytokine, which 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 gamma chain (gC). 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 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 on the first tryptophan. We furthermore demonstrate that a sugar chain bridge the two fibronectin domains which constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including the mannosylation. The glycan thus transforms the V-shaped receptor into a A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif

Interferons (IFNs) play a major role in orchestrating the innate immune response towards viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been described in a multitude of species, from bony fish to mammals. However, our current knowledge about the molecular function of fish IFNs as well as their evolutionary relationship to tetrapod IFNs is limited. Here we establish the 3D structure of zebrafish IFN1 and IFN2 by crystallography. These high-resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs which play an immediate antiviral role: type I IFNs (e.g. IFN-α and IFN-β) and type III IFNs (IFN-λ), and each type is characterized by its specific receptor usage. Similarly, two groups of antiviral IFNs with distinct receptors exist in fish, including zebrafish. IFN1 and IFN2 represent group I and group II, respectively. Nevertheless, both structures reported here reveal a characteristic type I IFN architecture with a straight F helix, as opposed to the remaining class II cytokines including IFN-λ, where helix F contains a characteristic bend. Phylogenetic trees derived from structure-guided multiple alignments confirmed that both groups of fish IFNs are evolutionarily closer to type I than to type III tetrapod IFNs. Thus, these fish IFNs belong to the type I IFN family. Our results also imply that a dual antiviral IFN system has arisen twice during vertebrate evolution.

Interferon lambda (IFN-l), også kaldet type III interferoner, tilhører gruppen af små helix rige cytokiner. De er i stand til at inducere en antiviral tilstand i kroppens celler. IFN-l signalerer via en receptor der består af to dele: Interleukin 10 receptor 2 (IL-10R2) og Interferon lambda receptor 1 (IFN-lR1). Bindingen til receptoren fører til dannelse af en lang række proteiner, der gør cellen mindre modtagelig for en infektion. I min phD demonstrerer jeg, at IFN-lR1 er nødvendig for at celler responderer på IFN-l. Jeg kortlægger desuden hvilke aminosyrer i IFN-l, der er vigtige for bindingen til receptor komplekset. Jeg har desuden bestemt strukturen af to interferoner fra zebrafisk og viser at disse er tættere beslægtet med type I interferoner end med type III interferoner