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Conformational switches of AXIN in Wnt/Beta-catenin signalling

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  • Full or part time
    Dr S Guettler
    Dr J Choudhary
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.

Conformational switches of AXIN in Wnt/Beta-catenin signalling

Project Description:
The Wnt/beta-catenin signalling network is highly conserved and controls important events in embryonic development as well as tissue homeostasis throughout life, and is dysregulated in the vast majority of colorectal cancers. The multi-protein beta-catenin destruction complex, composed of the scaffolding proteins AXIN (AXIN1/2, axis inhibition proteins 1/2) and APC (adenomatous polyposis coli), the kinases CK1 (casein kinase 1) and GSK3 (glycogen synthase kinase 3), and newly synthesised beta-catenin captured in the cytoplasm, initiates the proteasomal degradation of beta-catenin, thereby limiting beta-catenin’s transcriptional activity. AXIN is the central scaffolding subunit of the destruction complex. A multi-domain protein, it binds all other destruction complex components and can undergo filamentous polymerisation to achieve high local concentrations required for efficient beta-catenin capture and degradation. Moreover, AXIN is thought to switch between different conformational states. The conformation-defining intramolecular interactions proposed for AXIN remain poorly characterised, as do their impact on destruction complex assembly and their regulation by post-translational modification (phosphorylation and poly(ADP-ribosyl)ation). The aim of this project is to understand how post-translational modification of AXIN controls AXIN conformation and oligomerisation, and thereby its ability to assemble protein complexes that govern Wnt/beta-catenin signalling. The core approach will comprise a complementary set of techniques: protein biochemistry, biophysics, structural proteomics and structural biology (primarily X-ray crystallography). Hypotheses arising from work with purified proteins will be tested in mammalian cells. This study will provide novel mechanistic insights into fundamental signalling processes that govern development, tissue homeostasis and tumourigenesis.
For general information on activities in our laboratory, please visit:
www.icr.ac.uk/our-research/researchers-and-teams/sebastian-guettler
www.sguettlerlab.org

Keywords /Subject Areas:
Protein biochemistry
Protein conformation and protein complexes
Biophysics
Structural biology
Signal transduction

Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.
See icr.ac.uk/phds to apply
Applications close 11:55pm UK time on Sunday 17th November 2019

Candidates must have a first class or upper second class honours BSc Honours/MSc in Biology, Biochemistry or Chemistry.



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