Cytokines and growth factors are a group of intercellular protein messengers with the important biological role of stimulating the proliferation and differentiation of a number of different cell types. Structural studies have revealed that some cytokines which are historically and biochemically quite distinct, including growth hormone, colony-stimulating factors, interferons and some interleukins are found to share a common similar structure framework (a helical bundle) and a common receptor type. The members of this structural family can be divided into three subfamilies. The details of the cytokine structural classification will not be discussed here and a nice summary of the cytokine structural classification can be found at the Cytokines Web by Simon M. Brocklehurst. Instead we will focus on the short chain 4-helical bundle family that is represented by interleukin-4 (IL-4), interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF).
Five structures of the short chain 4-helix bundle subfamily have been determined in order to understand how these molecules bind to their receptors and facilitate signal transduction. We will focus on three of those structures in this report, namely IL-2, IL-4 and GM-CSF. A striking feature of these proteins is that there is very little amino acid sequence similarity between them. Despite this low level of sequence similarity, they are all functionally similar, all being extracellular signaling molecules via binding to homologous receptors; they are also structurally similar, all having a helical bundle of unique topology; and they are genetically similar, most having separate exons encoding the following structural elements: helix A; the A-B crossover; helices B and C; the C-D crossover and helix D (the up-up-down-down topology). An understanding of how diverse sequences can adopt the same fold are important to assess the structure function relation.
October 25, 1996.