The structure of IL2 bound to the three chains of the IL2 receptor and how signaling occurs
The interleukin-2 molecule and receptor were the first of the interleukins to be discovered and characterized at the molecular level. Now after 20 years of effort, two groups have succeeded in determining the structure of IL2 bound to the external domains of the three receptor chains in a quaternary complex. What do we know now that we did not know before this structural information was available, and how do these new data help us to develop new therapies?
In the early 1980s, soon after we had characterized the IL2 molecule as a 15.5 kDa variably glycosylated protein[1,2], had purified it to homogeneity, and had discovered and characterized the IL2 receptor (IL2R), our attention turned to trying to determine exactly how IL2 binding to its receptor leads to signals that promote cellular proliferation. One approach to this question involved determining the 3-dimensional (3D) structures of the IL2 molecule and the IL2R via X-ray crystallography.
However, it took more than a decade for us and others to discover that the IL2R is comprised of three distinct noncovalently linked chains, termed alpha (α, CD25), beta (β, CD122) [5-7], and gamma (γ, CD132). Subsequently, as the cDNAs encoding each chain became available, we began to collaborate with Ian Wilson of the Scripps Research Institute to try to determine the structures of these molecules. More...
The Cancer Cathedral
The concept that interleukins mediate their effects on target cells by means of interacting with specific cellular receptors was first introduced with the discovery and characterization of the IL2 receptor (IL2R) in 1981. Subsequently over the course of the 1980s the structure and function of the three IL2R chains were elucidated, and many additional interleukin receptors were discovered. Thereafter, the 1990s focused on experiments that discovered and characterized the intracellular signaling molecules and transcription factors activated by the interleukin-receptor interactions.
The foundations of the cancer cathedral were laid almost a half-century ago and are attributable to the work of a single young scientist, Peter Nowell of the University of Pennsylvania. In 1960 Nowell discovered that lymphocytes were capable of proliferating in response to the mitogenic plant lectin phytohemagglutinin (PHA), an extract from kidney beans used to agglutinate Red Blood Cells (RBCs). Prior to this discovery, lymphocytes were described in textbooks as differentiated, end stage cells incapable of self renewal.
Of course, just prior to Nowell's report, Macfarlane Burnet had postulated that lymphocytes were the fundamental cells comprising the immune system, and as a central tenet of his Clonal Selection Theory, he proposed that lymphocytes had to proliferate so that the clones of antigen-reactive cells could expand, a change in the whole cell population necessary before an efficacious response to the antigen could occur. More...