Oral Presentation 26th ACMM “2020 Visions in Microscopy”

The structure of the interleukin-11 signalling complex guides therapeutic design (#23)

Riley D. Metcalfe 1 , Eric Hanssen 1 2 , Kaheina Aizel 1 , Andrew P. Leis 2 , Courtney O. Zlatic 1 , Paul R. Gooley 1 , Tracy L. Putoczki 3 4 5 , Michael D.W. Griffin 1
  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
  2. Advanced Microscopy Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
  3. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkvile, Victoria, Australia
  4. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

The cytokine interleukin (IL)-11 is a therapeutic target in several diseases, including gastrointestinal cancer. IL-11 is an IL-6 family cytokine member that signals through the shared cell-surface receptor glycoprotein (gp) 130. Our laboratory has previously solved the structure of IL-11 and IL-11Rα, which has provided insights into the mechanism of cytokine engagement by IL-11Rα. 

We have solved the 3.5 Å cryoEM structure of the IL-11 signalling complex. The complex is a ~170 kDa hexameric complex consisting of two copies each of IL-11, the IL-11 specific receptor IL-11Rαand gp130. Our structure allows us to map the interfaces in the complex in detail and reveal mechanistic differences in receptor engagement between IL-11 and other cytokines, particularly in the engagement of the shared receptor gp130. We have complemented our cryoEM complex with extensive biophysical analysis of the complex, to understand solution stoichiometry and the thermodynamic mechanisms underpinning formation of the complex. We have also solved a ~4 Å structure of the complex using X-ray crystallography, which provides complementary insights to the cryoEM structure.

Our structure will allow us to better understand the structural mechanisms underpinning IL-11 signalling, which will guide the development and characterisation of new therapeutics.