ArticleNature communications2025
Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Interferon lambda in anti-viral defense and cancer: dual roles, mechanism and therapeutic potential.Journal of translational medicine · 2026Review
- Targets of protective immunity and opportunities in hepatitis C virus vaccine development.Nature reviews. Immunology · 2026Review
- IFN-λ4 Exhibits Differential Induction and Antiviral Activity in RSV and HMPV Infections.Viruses · 2026Article
- Geometric Tuning of Cytokine Receptor Association Modulates Synthetic Agonist Signaling.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface display to affinity-mature IL10Rβ and solve the 72 kilodalton structures of IFNλ4 (3.26 Å) and IFNλ3 (3.00 Å) in complex with their receptors IFNλR1 and IL10Rβ using cryogenic electron microscopy. Comparison of the structures highlights differences in receptor engagement and reveals a distinct 12-degree rotation in overall receptor geometry, providing a potential mechanistic explanation for differences in cell signaling, downstream gene induction, and antiviral activities. Further, we perform a structural analysis using molecular modeling and simulation to identify a unique region of IFNλ4 that, when replaced, enables secretion of the protein from cells. These findings provide a structural and functional understanding of the IFNλ4 protein and enable future comprehensive studies towards correcting IFNλ4 dysfunction in large populations of affected patients.
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Registered trials
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