Structural Biology, Walter and Eliza Hall Institute
○Thomas PJ Garrett Trevor Huyton Cindy S Luo Mei-zhen Lou Jian-guo Zhang Douglas J Hilton Nicos A Nicola

The gp130/IL-6 family form the largest known cooperative group of cytokines and receptors, and these molecules act in a wide variety of cell types, including embryonic stem cells, neurones, bone, muscle and breast epithelium. Cell signalling is usually initiated by the cytokine first binding a cytokine-specific non-signalling receptor. Next, signalling subunits are recruited into a high affinity cell-surface complex of between 3 and 6 molecules. In this family, signalling occurs via two distinct mechanisms. Some cytokines, such as IL-6 and IL-11, are capable of signalling via the gp130 receptor alone. However, most require a second signal receptor, such as the leukemia inhibitory factor receptor (LIFR). Questions still remain about the specificity of these multifunctional cytokines and how cytokine-specific signals can be transmitted by relatively few signalling molecules.
We have determined the crystal structure of the LIR:LIFR complex at 4.3 A resolution which shows a novel contact between the cytokine and an immunoglobulin-like domain of the receptor. This structure is the largest fragment to date of a cytokine receptor and, in combination with previously determined structures and EM studies, it enables us to build an accurate model of the high-affinity heteromeric signalling complex. This structure also reveals how LIF can act a master cytokine and modulate the activity of other cytokines in this family.