WEHI PhD Completion Seminar hosted by Dr Nadia Kershaw
Kaiseal Sarson-Lawrence
PhD Student – Kershaw Laboratory, Structural Biology division – New Medicines & Advanced Technologies Theme, WEHI
Structural studies of type I cytokine receptors
Davis Auditorium
Join via SLIDO enter code #WEHIphdcompletion
Including Q&A session
Followed by refreshments in Tapestry Lounge
Hematopoiesis is a complex process by which the full complement of mature blood cells are produced from a small population of hematopoietic stem cells in the bone marrow. Cytokine signalling plays a crucial role in hematopoiesis and at least 14 different cytokines are involved in determining the fate of hematopoietic stem cells. Cytokines act on cells by binding and oligomerising cytokine receptors on the cell surface. This oligomerisation activates intracellular JAK kinases that kick off a signalling cascade resulting in a cellular response. As cytokine binding is the critical first step in receptor activation, understanding how different cytokines bind to their receptors and how this extracellular binding event translates into an intracellular signal is fundamental to understanding hematopoietic diseases and designing therapeutic molecules.
My PhD work has focused on using cryogenic electron microscopy (cryo-EM) to study the mechanism of cytokine binding and receptor activation of two hematopoietic cytokine receptors. The first receptor is the thrombopoietin receptor (TPOR) which binds the cytokine thrombopoietin (TPO) and is a key regulator of megakaryocyte and platelet development. This receptor contains a unique duplication of its ligand binding domain not present in any other cytokine receptor. While the structure of the cytokine was previously determined by X-ray crystallography, the structure of the receptor and receptor-cytokine complex were elusive. The second receptor in my PhD project was the granulocyte colony stimulating factor receptor (GCSFR), which is activated by the GCSF cytokine and belongs to the “tall” family of cytokine receptors. This family is characterised by three additional fibronectin type-III domains in the extracellular domain which extends the receptor out from the cell membrane. Although a partial structure of the GCSFR-GCSF complex had been determined previously, how the membrane-proximal domains of the receptor interact was unknown.
My research has resulted in the first experimentally determined structures of the entire extracellular domains of both the TPOR and GCSFR receptors in complex with their cytokines. These structures and the corresponding biophysical data have improved our understanding of how these two receptors are activated by their cytokines.
