Structure Analysis of the IL-5 Ligand-Receptor Complex Reveals a Wrench-like Architecture for IL-5Rα

Abstract

Interleukin-5 (IL-5) is the key mediator for the function of eosinophil granulocytes, whose deregulation is characteristic of hypereosinophilic diseases and presumably contributes to allergic asthma. IL-5 signaling involves two transmembrane receptors, IL-5Rα and the common β chain, which upon formation of the ternary complex activate the JAK/STAT signaling cascade. To investigate the mechanism underlying ligand-receptor recognition, we determined the structure of IL-5 bound to the extracellular domain of IL-5Rα. IL-5 makes contact with all three fibronectin III-like domains of IL-5Rα, with the receptor architecture resembling a wrench. Mutagenesis data provide evidence that this wrench-like architecture is likely preformed. The structure demonstrates that for steric reasons, homodimeric IL-5 can bind only one receptor molecule, even though two equivalent receptor-binding sites exist. In regard to strong efforts being made to develop IL-5 antagonists for treating asthma and hypereosinophilic diseases, the advances in molecular understanding provided by this structure are of greatest value.

OGlcNAcylation and Phosphorylation Have Opposing Structural Effects in tau: Phosphothreonine Induces Particular Conformational Order

“…PGSPG(S/T) sequences in the PDB are observed as α-helix nucleation sites, with the Ser side chain and SPG(S/T) main chain oxygens acting as hydrogen bond acceptors to nucleate (N-cap) the N-terminus of an α-helix (e.g., glutaminyl cyclase (pdb 3si0), interleukin-5 receptor (pdb 3qt2)). 20 Phosphorylation has been observed to disrupt α-helix formation when the phosphorylation site is at an internal site in α-helices. 21 In contrast to the results above, in this case, the diethylphosphate, which induced increased α-helix, was structurally divergent from OGlcNAcylation.…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…3A depicts a model of the ternary complex, based on our ternary complex crystal structure (26), of a partially refined crystal structure of the GM-CSF:GMR-α binary complex and the crystal structure of the homologous IL-5 receptor alpha subunit (27). To visualize how anti-GM-CSF mAbs could interfere with the bioactivity of GM-CSF and its formation of a signaling complex with the GM-CSF receptor, we used Pisa (Version 1.37; www.ebi.…”

“…However, the GMR-α extracellular region in this complex was incomplete, with only the extracellular domain 3 (D3) of GMR-α well defined (26). Thus, extracellular domains 1 [N-terminal domain (NTD)] and 2 (D2) of GMR-α were modeled based on a partially refined crystal structure of the GM-CSF:GMR-α binary complex and the crystal structure of the homologous IL-5 receptor α subunit (27). Our GM-CSF:GMR-α binary complex data suggest that the GMR-α NTD-D2 linker is flexible and that the NTD may adopt a variety of orientations with respect to D2 and D3.…”

Insights into Cytokine–Receptor Interactions from Cytokine Engineering

“…In the βc system, an unprecedented dodecameric signaling complex of granulocyte macrophage colony-stimulating factor (GM-CSF) bound to GM-CSF-Rα and βc (55) appears to be driven by a broad network of additional interactions that could be specifically targeted in engineering βc cytokines. Several cytokines including IL-5 and IL-13 have an additional site of contact on top of their helical bundle with a top-mounted third Ig domain of their alpha receptors that clearly represents an engineerable site ( Figure 1 ) (36, 56, 57). IL-2 and IL-15 are the only cytokines known to possess a specific third receptor subunit (IL-2Rα and IL-15Rα, respectively) that differs markedly from typical CHR-containing receptors in both structure and mode of cytokine interaction (2, 37, 58).…”