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Thomas Leonard
Dr. Thomas Leonard

Max Perutz Labs
Position: Professor

T +43 1 4277 52205
thomas.leonard@meduniwien.ac.at

Further Information

Keywords

Allosteric Regulation; Lipids; Membranes; Protein Kinases; Structure-Activity Relationship

Research group(s)

Research interests

Physiological processes are driven by the coordinated action of organs, tissues and cells. Coordination of these activities allows organisms to respond appropriately to their changing environment. Within cells themselves, important metabolic processes are often compartmentalised by membranes, which necessitates the flow of information between compartments. How is this information integrated into the appropriate downstream response? We try to understand the basic principles that govern the flow of information in cells with particular emphasis on the role of lipid second messengers. By understanding the mechanisms by which these signals are transduced and propagated, we can better answer why and how things go wrong in disease.


Techniques, methods & infrastructure

We study how lipids regulate the activity of signaling enzymes, including both protein kinases and phosphatases. We use biochemical and cell biological assays supported by biophysical and structural techniques to deduce how, where, and when the signal is transduced. Our work is underpinned by quantitative biochemistry performed with precisely defined macromolecules. The insights we derive have the potential to rationalize disease pathogenesis at the molecular and atomic levels. For example, in the pro-growth and survival kinase Akt, we have characterized the mechanism by which a mutation associated with cancer and overgrowth disorders leads to kinase activity that is both spatially and temporally de-regulated. Determining how specific mutations drive the development of disease is essential for effective therapeutic intervention.


Grants

  • Microtubule-associated serine/threonine kinases in health and disease (2023)
    Source of Funding: FWF (Austrian Science Fund), Principal Investigator Project
    Principal Investigator
  • Phosphoinositide-dependent kinase 1: master growth regulator (2022)
    Source of Funding: FWF (Austrian Science Fund), Principal Investigator Project
    Principal Investigator
  • PI3K signaling- navigating upstream and downstream of Akt' (P 33066 (2019)
    Source of Funding: FWF (Austrian Science Fund), Principal Investigator Project
    Principal Investigator
  • Structure, function and regulation of Protein Kinase D (2018)
    Source of Funding: FWF (Austrian Science Fund), Principal Investigator Project
    Principal Investigator
  • Signaling Mechanisms in Cellular Homeostasis (2017)
    Source of Funding: FWF (Austrian Science Fund), Doctoral Program
    Principal Investigator
  • Lipid-activated kinases in cell shape and motility (2015)
    Source of Funding: FWF (Austrian Science Fund), Stand-Alone Projects
    Principal Investigator

Selected publications

  1. Reinhardt, R. et al. (2023) ‘PKD autoinhibition in trans regulates activation loop autophosphorylation in cis’, Proceedings of the National Academy of Sciences, 120(7). Available at: https://doi.org/10.1073/pnas.2212909120.
  2. Truebestein, L. et al. (2023) ‘Structure and regulation of the myotonic dystrophy kinase-related Cdc42-binding kinase’, Structure, 31(4), pp. 435-446.e4. Available at: https://doi.org/10.1016/j.str.2023.02.002.
  3. Levina, A. et al. (2022) ‘Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation’, Nature Communications, 13(1). Available at: https://doi.org/10.1038/s41467-022-29368-4.
  4. Truebestein, L. et al. (2021) ‘Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation’, Proceedings of the National Academy of Sciences, 118(33). Available at: https://doi.org/10.1073/pnas.2101496118.
  5. Pokorny, D. et al. (2021) ‘In vitro reconstitution of Sgk3 activation by phosphatidylinositol 3-phosphate’, Journal of Biological Chemistry, 297(2), p. 100919. Available at: https://doi.org/10.1016/j.jbc.2021.100919.