A novel dimer configuration revealed by the crystal structure at 2.4 Å resolution of human interleukin-5

Abstract

Interleukin-5 (IL-5) is a lineage-specific cytokine for eosinophilpoiesis and plays an important part in diseases associated with increased eosinophils, such as asthma. Human IL-5 is a disulphide-linked homodimer with 115 amino-acid residues in each chain. The crystal structure at 2.4 A resolution reveals a novel two-domain structure, with each domain showing a striking similarity to the cytokine fold found in granulocyte macrophage and macrophage colony-stimulating factors, IL-2 (ref. 5), IL-4 (ref. 6), and human and porcine growth hormones. IL-5 is unique in that each domain requires the participation of two chains. The IL-5 structure consists of two left-handed bundles of four helices laid end to end and two short beta-sheets on opposite sides of the molecule. Surprisingly, the C-terminal strand and helix of one chain complete a bundle of four helices and a beta-sheet with the N-terminal three helices and one strand of the other chain. The structure of IL-5 provides a molecular basis for the design of antagonists and agonists that would delineate receptor recognition determinants critical in signal transduction. This structure determination extends the family of the cytokine bundle of four helices and emphasizes its fundamental significance and versatility in recognizing its receptor.

Interleukin‐6: Structure‐function relationships

“…IFN-/3 has a fifth helix in the CDloop (Senda et al, 1995), while IFN-y and IL-10 have six helices which form an intercalating dimer, sharing the fifth and sixth helices across the dimer (Zdanov et al, 1996). IL-5, in the short-chain class, also forms an intercalating dimer that is disulfide-linked, sharing the second &strand and helix D (Milburn et al, 1993).…”

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Receptor Epitope Usage by an Interleukin-5 Mimetic Peptide

“…Extensive mutational analyses have identified recognition epitopes on both IL5 and IL5R␣, and the interaction can be envisioned by relating structure to function of these epitopes. IL5 is a symmetric homodimer in which each helical bundle domain is composed of three helices (A-C) from one chain and one (D) from the other (14). The binding epitope on IL5 for IL5R␣ is mapped on the structure, showing the importance of charged residues in helix B (His 38 , Lys 39 , and His 41 ), the CD turn (Glu 88 , Glu 89 , Arg 90 , and Arg 91 ), and helix D (Glu 110 ) for IL5R␣ binding (15)(16)(17).…”

IL-5 and IL-5 receptor in asthma

“…It contains 4 exons which encode a peptide of 124 amino acids (Azuma et al 1986 ). IL-5 is a monomer which exists functionally as an antiparallel homodimeric glycoprotein linked by 2 disulfide bonds and has a tertiary crystalline structue consisting of 4 alpha helices (Milburn et al 1993). The exon structure, primary secondary and tertiary protein sequences, cell membrane receptors and intracellular signal transduction pathways of IL-5 are similar with those from the IL-4 cytokine family, thereby suggesting that they are evolutionary related cytokines (Milburn et al 1993, Kosugi et al 1995.…”

“…IL-5 is a monomer which exists functionally as an antiparallel homodimeric glycoprotein linked by 2 disulfide bonds and has a tertiary crystalline structue consisting of 4 alpha helices (Milburn et al 1993). The exon structure, primary secondary and tertiary protein sequences, cell membrane receptors and intracellular signal transduction pathways of IL-5 are similar with those from the IL-4 cytokine family, thereby suggesting that they are evolutionary related cytokines (Milburn et al 1993, Kosugi et al 1995. Therefore, it is not surprising that these cytokines also share cellular sources and functional activities and are all important in the co-ordinated immune defense against parasitic infection.…”