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EASTBIO Understanding and exploiting tubulin diversity using chemical tools


School of Biological Sciences

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Dr Julie Welburn , Prof A N Hulme No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Microtubules are long polymers important for cell division, intracellular transport and polarity. Many isotypes of microtubules co-exist in eukaryotic cells and levels of expression vary with the cell type. Growing evidence shows different isotypes have different properties, leading to potentially distinct functions of tubulin in cells. This gives rise to a “tubulin code” hypothesis and raises many questions about basic tubulin biology but also in the specificity of microtubule cytoskeleton drug targeting to disrupt cellular processes and for therapeutic/commercial purposes.

In this project, the student will express different tubulin isotypes using a recombinant system to generate isotype-pure tubulin from human and Drosophila, and assess their sensitivity and affinity to known tubulin drugs using in vitro reconstitution and fluorescence anisotropy. The student will also have the opportunity to determine the cryo-EM structure of isotype-specific microtubules using our in-house EM facilities and study the mechanical properties of these isotype-pure microtubules, using AFM.

Using the chemical expertise of the Hulme lab, the student will then synthesize and optimize nocodazole derived compounds,[1] and macrocyclic compounds targeting the maytansine sub-site[2,3] to selectively target specific isotypes.[4] Computational approaches will be used to optimize the molecules. The student will first characterise the compounds biophysically with purified tubulin and test its activity on microtubule dynamics and assembly in vitro. From this work, the student will be able to hypothesize how drugs may fail to work in certain cell types, while the results will offer them opportunities to improve small molecule inhibitors based on isotype specificity and expression patterns.

Development Opportunities
This project enables a motivated Ph.D. student to apply chemistry, physics, cell biology, biochemistry and in vitro reconstitution assays to investigate the molecular properties of tubulin isotypes. These results will have strong implications for our understanding of cytoskeleton biology and the synthesis and optimization of macrocyclic drugs for personalized medicine, where microtubule-targeting drugs are often used to treat cancers and in agriculture, where microtubule-targeting drugs are used as pesticides.

Welburn.bio.ed.ac.uk
https://hulmegroup.wordpress.com

The School of Biological Sciences is committed to Equality & Diversity: https://www.ed.ac.uk/biology/equality-and-diversity

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Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition fees. The fee difference will be covered by the University of Edinburgh for successful international applicants. Please refer to UKRI website (https://www.ukri.org/our-work/developing-people-and-skills/find-studentships-and-doctoral-training/get-a-studentship-to-fund-your-doctorate/) and Annex B of the UKRI Training Grant Terms and Conditions (https://www.ukri.org/wp-content/uploads/2020/10/UKRI-291020-guidance-to-training-grant-terms-and-conditions.pdf) for full eligibility criteria.

References

[1] An overview of tubulin modulators deposited in protein data bank: H. Guo, X. Li, Y. Guo, L. Zhen, Med. Chem. Res., 2019. 28:927-937.
[2] Self-assembly of Disorazole C1 Using a One-pot Alkyne Metathesis Homodimerization Strategy: K. J. Ralston, H. C. Ramstadius, R. C. Brewster, H. S. Niblock, A. N. Hulme, Angew. Chem. Int. Ed. 2015. 54:7086-7090.
[3] A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin: G. Menchon, A. E. Prota, D. Lucena-Agell, P. Bucher, R. Jansen, H. Irschik, R. Müller, I. Paterson, J. F. Díaz, K.-H. Altmann, M. O. Steinmetz, Nature Commun. 2018. 9: 2106.
[4] Human β-Tubulin Isotypes Can Regulate Microtubule Protofilament Number and Stability: S. C. Ti, G. M. Alushin, T. M. Kapoor. Dev Cell. 2018. 47:175-190.
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