Phylogeny of a growth hormone-like cytokine superfamily based upon 3D structure.

Cytokines are of central importance in the regulation of hematopoiesis, immunity, inflammation, tissue remodeling, and embryonic development. Cytokine research is expected to provide the key to pharmacological manipulation of the immune response and commands the attention of a massive and highly focused biotechnology industry. Based upon the hypothetical secondary and tertiary structures, a superfamily of growth hormone (GH)-like cytokine was identified previously. Here, we report the phylogeny of this superfamily based upon 3D structural data from the Protein Data Bank. First, a retrieving program is designed to abstract their secondary structures and associated atomic coordinates. Helices, digitized as vectors in the Cartesian coordinate system, are collected from the retrieved atomic coordinates at the alpha carbons of the protein backbone. Then the scalar value and vector angle against the reference vector, usually the first vector, are calculated. Furthermore, cluster analysis among various cytokines is performed on their helical scales and helical angles. As a result, GH is close to the cluster formed by ciliary neurotrophic factor and granulocyte colony-stimulating factor (CSF); leptin and erythropoietin are in descending order close to the cluster formed by interleukin (IL)-6 and IL-10; the former seven members in the two subgroups above join together and form one group with leukemia inhibitory factor; granulocyte-macrophage CSF, IL-2, IL-4, and IL-5 are in descending order close to the cluster formed by IL-3 and macrophage CSF; and the latter six members form another group. Finally, it is demonstrated that the phylogeny of GH-like cytokines above is consistent with the evolutionary relationship of their gene organization, gene localization, receptor module composition, and receptor module compatibility.