1.2 Four helix bundle cytokines and their receptors.

1.2.1 Structure of ligands. Cytokines that fall into the four-helix bundle category fold as compact globular proteins with a core of four amphipathic alpha helices. By convention the helices are labelled A through to D; the three interconnecting loops are termed AB, BC and CD. The topology of these proteins follows a peculiar up-up-down-down  helical arrangement (figure 2) such that the AB and CD loops are long and both N and C termini are at one end of the bundle. The helix bundle can be thought of consisting of two pairs of anti-parallel helices namely A, D and C, B, which stack against each other to complete the bundle.

Four helix bundle cytokines can be subdivided into two structural categories; Short Chain or Long Chain. The two groups are delineated by differences in general structural features which are; the length of their core helices, the packing angle between the two pairs of helices, and the structural features of the interconnecting loops {Sprang, 1993 #2938}. The long chain group have helices of 10-20 residues and packing angles of ~18o, whereas the short chain group have helices of 10-15 amino acids with AD:CD packing angles of ~35o, and can display beta structures in the long AB and CD loops. Examples of members in the LC and SC groups are illustrated in fig*****. The peculiar topology of helical cytokines lends itself as a multivalent structure, through the “sticky” nature of the core amphipathic helices and the stable compact nature of the helical bundle.