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. 2011 Aug;85(16):8181-7.
doi: 10.1128/JVI.00521-11. Epub 2011 Jun 8.

Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates

Ole Jensen Hamming  1 , Georges Lutfalla, Jean-Pierre Levraud, Rune Hartmann
Affiliations

Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates

Ole Jensen Hamming et al. J Virol. 2011 Aug.

Abstract

Interferons (IFNs) play a major role in orchestrating the innate immune response toward viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been reported 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 three-dimensional (3D) structure of zebrafish IFNϕ1 and IFNϕ2 by crystallography. These high-resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs that play an immediate antiviral role: type I IFNs (e.g., alpha interferon [IFN-α] and beta interferon [IFN-β]) and type III IFNs (lambda interferon [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. IFNϕ1 and IFNϕ2 represent group I and group II IFNs, 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.

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Figures

Fig. 1.
Fig. 1.
Structure of the zebrafish interferons. (A) Cartoon representation of the structure of IFNφ2 (PDB accession number or entry code 3PIW). The structural elements are labeled A through F. The two disulfides are shown in yellow. (B) Electron density (2σ) of a fraction of the F helix in IFNφ2 is shown. Residues from helix F are labeled. (C) Cartoon representation of the structure of IFNφ1 (PDB entry code 3PIV). The structural elements are labeled A through F. The single disulfide is shown in yellow. (D) Electron density (2σ) of a fraction of the F helix in IFNφ1 is shown. Residues from helix F are labeled. (E) Comparison of the structures of IFNφ1 (red) and IFNφ2 (cyan). The two molecules have been superimposed in coot using SSM superimpose.
Fig. 2.
Fig. 2.
Comparison of the zebrafish interferons to mammalian type II cytokines. (Top) Comparison of IFNφ1 to human IFN-α2 (PDB accession number or entry code 1RH2), IFN-λ3 (PDB entry code 3HHC), and IL-10 (PDB entry code 2H24). (Bottom) Comparison of IFNφ2 to human IFN-α2, IFN-λ3, and IL-10. The molecules have been superimposed in coot using SSM superimpose.
Fig. 3.
Fig. 3.
The CAWE motif of IFNφ2. Conserved residues in type I interferons in the vicinity of the CAWE motif are shown as sticks. The residues in the CAWE motif are colored orange. The highly conserved aromatic residue (Phe) is colored red. Visible helices and loops are labeled. See text for details.
Fig. 4.
Fig. 4.
Structure-guided alignment of class II cytokines. (A) Multiple alignment of zebrafish IFNφ1 and IFNφ2 with human class II cytokines, established from superimposing crystallographic structures. Amino acids have been colored according to the principal orientation of the side chain, using the code at the bottom of the alignment; if the orientation of the side chain is ambiguous or unknown, the amino acid was left in black. Alpha-helical regions are shown on a yellow background. Cysteines engaged in disulfide bridges are depicted in bold type. Exon boundaries are represented by underlined letters (the last amino acid coded by an exon and the first amino acid coded by the next exon). Gaps introduced to maximize alignment are indicated by dashes. (B) Phylogenetic tree obtained using a distance (neighbor-joining) method, deduced from the alignment in panel A. The “type I IFN clade” is circled. Bar, 0.5 amino acid substitutes. (C) Consensus cladograms obtained from the alignment in panel A, with the IFN-γ sequence chosen as an outgroup. For each node, the bootstrap support values (out of 1,000 replicates) are given for distance, parsimony, and maximum likelihood methods by the top, middle, and bottom numbers, respectively.
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References

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