How IL-5, IL-3 and GM-CSF regulate blood cell growth and function

The receptor system for IL-5 is shared with two related cytokines, IL-3 and GM-CSF, which are also involved in the regulation of blood cell formation and inflammation. One of the major problems in cell signalling is to understand how these cytokines regulate blood cell growth and function by binding and activating their cell-surface receptors. In a collaborative project with Paul Carr and David Ollis (Research School of Chemistry) using X-ray crystallography we have determined the structure of the complete extracellular domain of the beta common receptor which is the major signalling entity of the IL-5 receptor and is central to the signalling of all three cytokines. The receptor was expressed in insect cells and its crystallization and derivatization involved extensive use of site-directed mutagenesis to improve crystal quality and to solve the phase problem. The novel dimer configuration of the receptor gives new insights into receptor activation. James Murphy is using site-directed mutagenesis to define the residues of the beta common receptor which are involved in forming the activated receptor complex. Peter Fineran, Alice Church, Sally Ford, Janine Inggs and Jane Olsen have prepared the activated complex of the closely related beta-IL-3 receptor. Further structural studies should give a better understanding of the process of receptor activation and provide opportunities to develop drugs capable of controlling this important receptor system. Such drugs could be useful in treating asthma, allergy or cancer.