Biochemistry & Biophysics | Molecular Cell Biology | Structural & Computational Biology
Structural Biology of Lipid-Activated Signal Transduction
Membranes are sites of intense signaling activity in eukaryotic cells. Essential processes such as autophagy, cytokinesis, exo- and endo- cytosis, and cytoskeletal remodeling depend on signal propagation at cellular...more
Membranes are sites of intense signaling activity in eukaryotic cells. Essential processes such as autophagy, cytokinesis, exo- and endo- cytosis, and cytoskeletal remodeling depend on signal propagation at cellular membranes. Dysregulation of signal transduction at these sites is the cause of a number of hereditary and non-hereditary diseases, including Coffin-Lowry syndrome, spinocerebellar ataxia, myotonic dystrophy, and various cancers. Over 500 kinases and 130 phosphatases regulate signal transduction by phosphorylating or dephosphorylating their target proteins. Given that the chemistry of phosphoryl transfer is conserved, there is a clear need for compartmentalization of what are essentially the same chemical reactions.
Of the more than 500 kinases, 54 contain known lipid-binding or membrane-interacting domains, and whilst much is known about how these proteins are targeted to cellular membranes, very little is known about how membrane engagement is coupled to signal transduction. We are using a spectrum of biophysical (including X-ray crystallography), biochemical, and cell biological techniques to investigate signal transduction at membranes. We have recently demonstrated the allosteric activation of Akt by the lipid second messengers PI(3,4,5)P3 and PI(3,4)P2 for the first time (Ebner and Lučić et al., Molecular Cell 2017).
One of the most important consequences of the activation of cell surface receptors is the generation of small molecule second messengers. In addition to the freely diffusible second messengers such as cAMP and inositol triphosphate (IP3), a number of cellular second messengers are lipids. Despite being of fundamental importance to the exquisite spatial and temporal regulation of many cellular processes, the molecular mechanisms of lipid-mediated signal transduction are not well understood. Our goal is to understand how lipid second messengers can turn on signaling pathways at the membrane. Many of the lipid responsive human protein kinases belong to the AGC family of kinases, of which paradigmatic lipid-activated kinases are Akt and protein kinase C (PKC). We would like to understand how lipid-engagement by these protein kinases is coupled to their activation at the molecular level. Ultimately, we hope to elucidate common principles of the molecular mechanisms that govern lipid-mediated signal transduction.
Fundamentally, we aim to describe signal transduction processes with deep mechanistic insight. By combining structure with quantitative in vitro biochemistry on rigorously validated samples, we can probe the structure-function relationship in absolute terms. We have recently applied these principles to study the Tec and Src family tyrosine kinases, work which has revealed a previously unknown switch in nucleotide binding that drives kinase activation (von Raußendorf et al., Scientific Reports 2017).
We are also interested in how signal transduction pathways are organized. Scaffolding of signaling proteins in the same pathway enhances specificity, promotes signal amplification by reducing noise, and, ultimately, improves signal propagation through the pathway. Membranes act as the scaffolds for many signaling reactions, including those involved in visual signaling in Drosophila and those involved in regulating cellular growth processes. Our studies are aimed at understanding how diverse signals are integrated, how substrate specificity is encoded not just at the kinase level, and the influence of the membrane environment on multi-component signaling hubs. This is an exciting area of research with frontiers in ageing, cancer, metabolic diseases such as diabetes, and obesity.
The Leonard lab is looking to recruit a new PhD student in the next VBC PhD selection (January 2018). We are looking for bright young talent fascinated by science. If you are interested in joining a team to work on fundamental questions in biological signal transduction, please get in touch! For further details, please see: https://www.training.vbc.ac.at/phd-programme/
2017 VBC PhD Award to Iva for her outstanding PhD thesis. Well deserved!
Congratulations Dr. Lučić on a successful PhD defence!
Congratulations to Linda on being awarded a Hertha Firnberg Postdoctoral Fellowship!
Congratulations Dr. von Raußendorf on a successful defence!
Congratulations to Daniel on travel scholarship to EMBO meeting!
Congratulations Iva on being awarded a Univie Thesis Completion Fellowship!
Congratulations to Iva on her Keystone short talk invitation!
Congratulations to Iva on travel scholarship to EMBO meeting!
von Raußendorf, Freia; de Ruiter, Anita; Leonard, Thomas A. (2017). A switch in nucleotide affinity governs activation of the Src and Tec family kinases Scientific reports.;7(1):17405. PMID: 29234112
Michael Ebner, Iva Lučić, Thomas A. Leonard, and Ivan Yudushkin (2017). PI(3,4,5)P3 Engagement Restricts Akt Activity to
Cellular Membranes MOL CELL;65(3):416-431. PMID: 28157504
Truebestein, Linda; Elsner, Daniel J; Fuchs, Elisabeth; Leonard, Thomas A (2015). A molecular ruler regulates cytoskeletal remodelling by the Rho kinases. NAT COMMUN;6:10029. PMID: 26620183
National Scientific Research Fund (FWF) Project
Project title: "Structure, Function, and Regulation of Protein Kinase D" (P 30584)
Hertha Firnberg Postdoctoral Fellowship (FWF)
Dr. Linda Trübestein is a recipient of a Hertha Firnberg Postdoctoral Fellowship (FWF).
Project title: "Bridging the Gap - Regulation of the Cytoskeleton by the DMPK kinases" (T 915)
Doctoral Program "Signaling Mechanisms in Cellular Homeostasis"
The Leonard Group is a member of the special doctoral program "Signaling Mechanisms in Cellular Homeostasis", reviewed and funded by the Austrian Research Fund FWF (start 2017).
National Scientific Research Fund (FWF) Project
Project title: "Lipid-activated kinases in cell shape and motility" (P 28135)
Boehringer Ingelheim Fonds PhD Fellowship
Daniel Elsner is a recipient of the prestigious BIF PhD Fellowship.
Freia von Raussendorf is a recipient of the Austrian Academy of Sciences DOC Fellowship
Freia von Raußendorf, PhD defence 2017
Iva Lučić, PhD defence 2017