Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons

Abstract

Summary Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human IFN variants signal through the same cell surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique amongst the cytokine receptor superfamily, but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor-points" interspersed amongst ligand-specific interactions that ‘tune’ the relative IFN binding affinities, in an apparent extracellular ‘ligand proofreading’ mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo

“…It is becoming apparent that subtle differences in the amino acid sequences of IFN-␣ subtypes can produce a significant effect on the binding affinity for the IFN-␣/␤ receptor, downstream signaling events, and antiviral efficacy (2)(3)(4)(5)82). Given that rhesus macaque IFN-␣2 sequences compared to human and SM/AGM IFN-␣2 are only 92 and 98% identical, respectively, future studies in macaques should consider using species-specific IFNs rather than human IFNs (83).…”

“…Interestingly, human IFN-␣ is not a single entity, but rather, the products of a multigene family encoding 12 IFN-␣ subtypes (1), all of which bind to the IFN-␣/␤ receptor. Each subtype binds the receptor using distinctive contacts (2), thereby eliciting distinct signaling events (3,4) and variable biological outcomes (5). While the unique affinity of the subtypes for each receptor subunit seems to contribute to differential downstream signaling, there appear to be additional factors influencing the unique outcomes elicited by individual subtypes that are currently not fully understood.…”

Distinct evolution process among type I interferon in mammals

“…This may be caused by the different ways that they interact with IFN receptor subunits. Despite their differences in sequence, IFNωdemonstrates little difference with IFNα in their expression, function, ternary complex structures with receptors, and abilities to induce ISGs (Thomas et al, 2011). Expressed by trophoblasts before they attach to the placenta, IFNτ is important to prevent the corpus luteum from degradation and, hence, ensuring the pregnancy continues, while IFNδ is expressed in conceptus and shows a potent ability to regulate pregnancy (Chelmońskasoyta, 2002;Roberts, 2007).It has been hypothesized that IFNτ is not virally inducible a nd that its function has no relationship to pathogenesis, which is quite different from the other multigene Type I IFNs, but recent research shows that bovine IFNτis an antiviral protein capable of inducing 2′-5′ OAS with less toxicity to the cells, which suggests that IFNτ could be a better drug than IFNα for patients suffering from viruses (Johnson et al, 2001).…”

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

“…Cells lacking one of the receptors lack normal IFN signaling (4,5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5)(6)(7)(8)(9)(10)(11)(12)(13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15).…”

“…However, recent work has disputed the pre-formation of IFNAR1 and IFNAR2 and has shown clear evidence for ligand-induced receptor dimerization (2,36). Still, IFN binding clearly induces a large conformational shift in IFNAR1, as evident from comparing the unbound to bound structures of the complex and from fluorescence quench and FRET experiments (7,37). Thus, although IFN is required to produce the ternary complex, the role of structural plasticity for signaling through the interferon receptor is not resolved.…”