Investigating the Structure and Regulation of Fibroblast Growth Factor Receptor 3 (FGFR3) (360G-Wellcome-109155_Z_15_A)

Receptor tyrosine kinases (RTKs) are cell surface receptors which play a critical role in cell proliferation, homeostasis and survival, mediated by initiation of intracellular signalling cascades in response to extracellular ligand binding. The fundamental importance of RTKs is underlined by the prevalence of pathologies associated with their dysregulation. Despite extensive research in the RTK field, there remain many unanswered questions with regards to the structural and dynamic mechanisms of activation and regulation, both in physiological and pathological settings. Crucially, the key question of how the binding of growth factor to the extracellular domain results in choreographed conformational transitions at the intracellular kinase domain to trigger downstream signalling remains an enigma. To elucidate this question, I will use cryo-electron microscopy to determine structures of full-length fibroblast growth factor receptor 3 (FGFR3), an RTK. Hsp90, a member of the cellular protein-folding machinery, is thought to regulate kinases and protect oncogenic variants from proteasomal degradation. Though glimpses of the mechanisms underlying kinase-(co)chaperone interactions are beginning to appear, the structural determinants of chaperone-dependence of kinases are unclear, especially for RTKs. Thus, in parallel, I will use NMR spectroscopy to investigate the dynamic interactions of the FGFR3 kinase domain with the Cdc37-Hsp90 chaperone system.