Přehled

Doctoral study program: Life Sciences (Faculty of Science, Masaryk University)

Supervisor: Konstantinos Tripsianes, Ph.D.

Annotation

Dishevelled (DVL) is the central hub of Wnt signal transduction that integrates and transduces upstream signals through distinct cytoplasmic cascades. Looking at the many DVL faces reported in literature, three salient features underlying its function in signaling can be highlighted: (1) it interacts with more than seventy binding partners, (2) it is heavily phosphorylated at multiple sites by at least eight different kinases, in particular by Ck1ε/δ after Wnt stimulation, and (3) it consistently forms puncta in the cytosol, that are phase-separated self-assemblies also called liquid droplets.

Our working hypothesis is that DVL conformational plasticity mediated by the order-disorder interactions allows the combinatorial integration of phosphorylation input, partners binding, self assembly in droplets, and allosteric coupling, to exquisitely control signal routing. We integrate structural biology (NMR, SAXS, X-ray, MS-HDX) and biophysical techniques (FRET, ITC, BLI) with cellular readouts (TopFlash, BRET) to understand DVL structure, function, and regulation. Candidates can choose among three open questions, that if resolved, will have significant impact on Wnt research.

Does disorder provide new contexts to structured domain(s) and, hence, enhance the DVL functional space associated with them?
Is there a direction, order or hierarchy in the phosphorylation of individual S/T sites and clusters in DVL?
What are the physical behaviors associated with intrinsic disorder and their connection to DVL liquid-liquid phase separation?

Recommended literature

  • Kravec M. et al. A new mechanism of posttranslational polyglutamylation regulates phase separation and signaling of the Wnt pathway protein Dishevelled. Embo J., 2024 (accepted)
  • Hanáková K. et al. Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs. Cell Commun. Signal., 2019. 17: p. 170
  • Harnoš J. et al. Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1. Nat. Commun., 2019. 10: p. 1804.

Research area: protein research in health, Wnt signalling, structural proteomics, mechanisms of protein function

Keywords: Wnt signaling, Dishevelled, Casein kinase, interactions, conformations, phosphorylations, dynamics, allostery, NMR, X-ray crystallography, SAXS, FRET, cryo-EM, native MS, MS-HDX.

Funding of the PhD candidate: GACR 2304

Requirements for candidate

  • Biomolecular NMR
  • Biochemistry
  • Molecular Cell Biology

Information about the supervisor: 3 PhD students, 34 publications, h-index 20

Information about the application process: https://www.ceitec.eu/ls-mm-phd/

Application webpage: https://www.ceitec.eu/dishevelled-internal-affairs-in-wnt-signaling/t11442

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