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If you thought that all it took to kick-start a signaling pathway was a ligand binding to a receptor, think again. How and when that binding occurs, it turns out, is what determines what happens inside the cell.

In a study published online in Cell today, Sherry LaPorte of Stanford University and colleagues describe the structure of the Interleukin-4 and Interleukin-13 (IL-4/13) cytokines and the complete set of receptors they bind, including the one receptor complex they have in common.

It's not very surprising that different ligands can act on the same receptor to trigger different signal cascades. But the authors' crystal structures reveal that identical receptors can distinguish between ligands that differ only slightly, such as the IL4 and IL-13 molecules. The receptor that IL-4 and IL-13 share is actually a composite of two receptors: the IL-14 receptor α and the IL-13 receptor α. Both are required to initiate a signal, but the IL-4 touches the IL-4 receptor first and with higher affinity, while IL-13 touches the IL-13 receptor first. The researchers think it's this slight difference in the order of contact and affinity that triggers one signaling pathway versus another.

Most ligands work by bringing receptors components together at the cell surface. For many receptors, that is sufficient for initiating a signal. This study shows that kick-starting a signaling pathway depends not just on activating the receptor, but also on the intricate differences in movement and binding on the extracellular face of the receptor, writes Alexander Wlodawer from the National Cancer Institute in a commentary accompanying the article.

Wlodawer, who was not involved in this research, told The Scientist that the study has important implications for drug design, since IL-4 and IL-13 initiate specific signaling pathways that are both important in allergy and asthma. Understanding the specific sequence of events that triggers one signal versus another will help drug makers design molecules that mimic that behavior. But, he added, researchers don't yet have the full picture of how molecules at the cell surface interact to determine the specificity and strength of the signal propagated within the cell.