Structural linkage between ligand discrimination and receptor activation by type I interferons.

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Type I interferons (IFNs) are crucial cytokines for innate immunity, antiviral defense, and anti-cancer responses.
• Sixteen human type I IFN variants signal through common receptors (IFNAR1/IFNAR2) but induce diverse physiological effects.

Purpose of the Study:

• To elucidate the structural basis for differential signaling of human type I IFNs through their shared receptors.
• To understand the molecular mechanisms underlying the distinct biological activities of various type I IFNs.

Main Methods:

• Crystal structure determination of human type I IFN (IFNα2 and IFNω) ternary signaling complexes with IFNAR1 and IFNAR2.
• Analysis of receptor-ligand interactions, including conserved "anchor points" and ligand-specific contacts.

Main Results:

• Revealed unique heterotrimeric architectures and recognition modes for type I IFN-receptor complexes, conserved across different IFNs.
• Identified a "ligand proofreading" mechanism involving conserved "anchor points" and ligand-specific interactions that modulate IFN binding affinity.
• Demonstrated that functional differences arise from receptor recognition chemistry and ligand-induced IFNAR1 conformational changes, impacting STAT phosphorylation and gene expression.

Conclusions:

• The structural and biochemical mechanisms explain how conserved receptor interactions lead to differential type I IFN biological activities.
• Understanding these precise molecular interactions offers insights into optimizing type I IFN-based therapies for viral infections and cancer.