Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering

William S. Grubbe, Bixia Zhang, Aileen Kauffman, Fabian Byléhn, Kasia Padoł, Hae-Gwang Jung, Seung Bum Park, Jessica M. Priest, Engin Özkan, Juan J. de Pablo, T. Jake Liang, Minglei Zhao and Juan L. Mendoza ()
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William S. Grubbe: University of Chicago
Bixia Zhang: University of Chicago
Aileen Kauffman: University of Chicago
Fabian Byléhn: University of Chicago
Kasia Padoł: University of Chicago
Hae-Gwang Jung: National Institutes of Health
Seung Bum Park: National Institutes of Health
Jessica M. Priest: University of Chicago
Engin Özkan: University of Chicago
Juan J. de Pablo: University of Chicago
T. Jake Liang: National Institutes of Health
Minglei Zhao: University of Chicago
Juan L. Mendoza: University of Chicago

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56119-y

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