Molecular basis of cytokine signalling--theme and variations

Cytokine receptors are crucial for the maintenance, regulation and growth of cells in multicellular organisms. As a common theme in cytokine signalling, single-span receptor chains are assembled in the cell membrane by a ligand enabling cross-activation of the aligned cytoplasmic receptor domains. Nature has created many variations of how this general principle is realized in a cell. Here we focus on cytokines of the four-helix bundle (interleukins) and cystine knot (transforming growth factor-beta/bone morphogenetic proteins) families. Upon activation, receptor chains can form duos, trios, quartets and even larger assemblies. The structure of the extracellular ligand-binding domain of a number of these receptor complexes has now been elucidated, providing the molecular basis for understanding the functional relevance of mechanistic diversity in a cellular context. Biochemical and structural data have revealed ligand recognition mechanisms. Contact sites are usually large and rather flat. A limited number of contact residues provide most of the binding free energy (hot spots). Leaks in hydrophobic seals appear to provide a mechanism for adjusting the affinity of a hot spot interaction (scalability). Bone morphogenetic protein ligands are often promiscuous and interact not only with receptors, but also with a multitude of modulator proteins, which inhibit or enhance bone morphogenetic protein signalling. Cytokine receptor systems offer promising targets for drug development. Information on the structure and the activation mechanism provides leads for developing biologicals, such as engineered cytokines, cytokine mutants acting as receptor antagonists and receptor extracellular ligand-binding domain-Fc fusion proteins. Possible indications exist in the areas of haematology, immunology, inflammation, cancer and tissue regeneration.