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Structural biology of carbohydrate-active enzymes linked to muscular dystrophy


Department of Chemistry

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Dr L Willems , Prof G Davies No more applications being accepted Funded PhD Project (Students Worldwide)
York United Kingdom Biochemistry Biophysics Cell Biology Molecular Biology Structural Biology

About the Project

Background

Proteins on the surface of cells are often modified with complex carbohydrate structures. These carbohydrates, named glycans, play key roles in a range of cellular processes including cell-cell and host-pathogen interactions. In this project, we will focus on a specific type of glycan that is unique to mammals and plays an essential role in neuromuscular tissue by linking the cell’s cytoskeleton with components of the extracellular matrix. The resulting cell-matrix interactions are vital for the proper function of muscle tissue and, consequently, loss of these interactions leads to muscular dystrophy.

A subset of muscular dystrophies is caused by genetic defects in the enzymes that are responsible for glycan biosynthesis, resulting in the incomplete assembly of the matrix-binding glycan. While the involvement of these enzymes in disease pathology has been well established, many aspects regarding their mechanism and the effects of disease-causing mutations remain poorly characterised. To better understand the roles of the various enzymes in disease pathology, we need to develop specific tools and methodologies to study their function at a cellular and molecular level.

Objectives

In this ERC-funded project, you will contribute to our multidisciplinary research program by studying the 3-D structure and activity of one of the glycan-biosynthesising enzymes that is involved in muscular dystrophy. Working with other team members, you will also evaluate enzyme probes and inhibitors generated in-house as novel research tools and use the insights from structural studies and activity assays to inform the design of new probes. These tools will then be used to develop assays to monitor enzyme activity in cells and tissues. Ultimately, the aim is to elucidate how specific mutations that are known to be causative for muscular dystrophy affect the enzyme’s properties in vitro as well as in a cellular context.

Experimental approach

You will express genes encoding a human glycosyltransferase and selected bacterial homologs using both bacterial and mammalian expression systems. You will then characterise the activity of the purified proteins using in vitro assays and solve their 3-D structures in complex with ligands and probes generated by other team members. You will also contribute to the design and analysis of new small molecule inhibitors and probes based on your observations. Finally, you will generate disease-relevant mutant enzymes and analyse the effects of single amino acid substitutions on the protein’s activity and structure.

Novelty and impact

Your work will provide fundamental insights into a specific form of glycosylation and the cellular pathway by which the glycan is biosynthesised and will help us better understand how certain genetic variations contribute to disease pathology. Your research will also address a clear gap in the current toolbox for studying this enzyme class by providing a platform to design and evaluate novel chemical tools. Furthermore, the work has potentially far reaching implications for disease diagnosis and the screening and evaluation of potential therapeutics.

Training

You will benefit from a truly interdisciplinary training environment and as part of York’s world-renowned York Structural Biology Laboratory (YSBL) you will receive excellent training in molecular biology and protein production, protein characterisation and modern structural biology (primarily X-ray, but CryoEM is also available). You will additionally be exposed to the work of team members in the areas of synthetic chemistry, cell biology and glycomics. You will be working closely together with other group members to integrate your work with the synthesis and the analysis of substrates and probes. Attendance at group meetings, departmental and YSBL seminars and relevant conferences will further strengthen your multidisciplinary training. All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/  

You should hold or expect to achieve the equivalent of at least a UK 2:1 degree in Chemistry or a related subject.  Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

This PhD is expected to start on 1 October 2021, however an earlier start date is possible if the candidate is available

HOW TO APPLY: to be considered for this PhD, you need to submit an application for a PhD in Chemistry by 10 February 2021 via this link: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3


Funding Notes

This project is funded by the European Research Council. Appointed candidates will be fully-funded for 3 years. The funding includes:
 Tax-free annual “UKRI level” stipend (£15,285 full time for 2020/21)
 UK tuition fees (£4,473 for 2021/22)
 Research support and training charges
International candidates (including from the EU) will be considered. From 1 August 2021, EU students will be charged fees at the overseas rate. If a student was appointed where overseas fees were charged, the fee difference would need to be covered from other sources. Overseas tuition fees for 2021 entry are £22,250. https://www.york.ac.uk/study/postgraduate-research/fees/

References

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students: https://www.york.ac.uk/chemistry/ed/.
For more project information, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution.
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