Creation of a biologically active interleukin-5 monomer.
Interleukin-5 (IL-5) specifically induces the differentiation of eosinophils, which are important in host defence and the pathogenesis of allergies and asthma. Structurally, IL-5 is a unique member of the short-chain helical-bundle subfamily of cytokines whose canonical motif contains four helices (A-D) arranged in an up-up-down-down topology. In contrast to other subfamily members, which fold unimolecularly into a single helical bundle, IL-5 forms a pair of helical bundles by the interdigitation of two identical monomers that contribute a D helix to the other's A-C helices. We predicted that the lack of bioactivity by an IL-5 monomer was due to a short loop between helices C and D which physically prevents unimolecular folding of helix D into a functionally obligate structural motif. Here we report that, by lengthening this loop, we have engineered an insertional mutant of IL-5 that was expressed as a monomer with biological activity similar to that of native IL-5. These studies demonstrate that all of the structural features necessary for IL-5 to function are contained within a single helical bundle.
Dickason
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Baylor College of Medicine, Department of Medicine, Houston, Texas 77030, USA.
Huston
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D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D003001:Cloning, Molecular; D003198:Computer Simulation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015848:Interleukin-5 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D018123:Receptors, Interleukin / Q000378:metabolism; D053649:Receptors, Interleukin-5; D018411:Spodoptera; D014407:Tumor Cells, Cultured
D015848:Interleukin-5; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5