The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement

Abstract

Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the β-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11–IL-11Rα complex.

Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11

“…Likewise, the IL-11Rα binding site (site-I) and the first gp130 binding site (site-II) of IL-11, previously identified through mutagenesis (175,176), are different in chemical character to IL-6, with site-I more hydrophobic (Figure 6B). Our recent structure of IL-11Rα ( Figure 6C) (174) revealed that the cytokine binding site of the receptor is more hydrophobic in character than IL-6Rα, consistent with the corresponding site of IL-11 and suggesting distinct mechanisms of cytokine engagement.…”

“…In contrast to IL-6, LIF and other IL-6 family cytokines, little was previously known about the structure of IL-11 or IL-11Rα. We reported the first crystal structure of IL-11 in 2014 (98) and have recently reported a higher-resolution structure of the cytokine (Figure 6A) (174). Our structures show that IL-11 is ∼5 Å longer than IL-6, suggesting differences in binding mode and geometry within the signaling complex.…”

“…No high-resolution structural data for the IL-11 signaling complex are currently available in the literature, although sequence analysis (121,177) and our structural data (174) show that IL-11Rα and IL-6Rα are structurally similar. The IL-11 signaling complex, like the IL-6 signaling complex, is thought to be hexameric, as shown by immunoprecipitation and electrophoresis (178).…”

“…Several of the mutations have been shown to impair correct processing and surface expression of the receptor (199). Molecular dynamics simulations using our IL-11Rα structure indicate that some mutations destabilize the receptor and may have indirect effects on the cytokine binding region (174).…”

“… The structure of IL-11. (A) Two views of the structure of IL-11 [PDB ID: 6O4O ( 174 )]. (B) Receptor-binding sites on IL-11, which have been identified through mutagenic studies on human and mouse IL-11.…”