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Development of chemical biology tools to study mammalian O-mannosylation pathways


Project Description

The field of chemical biology aims to design and synthesize chemical tools (such as inhibitors, substrate mimics, or enzyme probes) to answer fundamental questions in biology. In this project, we are focusing on creating tools to study some of the key enzymes responsible for synthesizing specific carbohydrate structures in cells.

Proteins on the surface of cells are often modified with diverse, complex carbohydrate structures. These carbohydrates, named glycans, play roles in a range of cellular processes including cell-cell and host-pathogen interactions. Glycans are synthesized by networks of multistep enzymatic pathways. This project focuses on enzymes that are involved in the biosynthesis of O-mannosyl glycans, a type of glycan in which a mannose sugar is first linked to a protein and is then further elongated into complex carbohydrate structures. The best studied O-mannosylated protein is α-dystroglycan (αDG), which plays essential roles in muscle tissue and the nervous system by linking the cytoskeleton with the extracellular matrix. Interest in this specific glycoprotein stems from the fact that defects in O-mannosylation cause a variety of congenital muscular dystrophies. In addition to αDG, another family of O-mannosylated proteins is that of the cadherins, proteins that control cell-cell adhesion and have been shown to play a role in pathogenic infections and cancers. Recent findings (2016/2017) revealed that the O-mannosyl glycans on these proteins are installed by a pathway separate from that dedicated to αDG, and that the initial mannose residue is not further elongated. However, it is unclear which enzymes are involved in this new pathway, and how cells decide which protein to target to which of the O-mannosylation pathways.

In this project, we aim to generate a new set of tools to enhance our understanding of the various cellular O-mannosylation pathways, by focusing on key enzymes that are responsible for synthesis of the mannose glycan. This research will be of interest not only to other researchers working in the field, but will also have a significant impact on clinical research by helping us better understand how specific clinical mutations in these enzymes contribute to disease.

In order to reach these goals, we will use an interdisciplinary approach that combines organic synthesis with biochemistry, basic cell biology and structural biology. The project consists of three parts:
1. Chemical synthesis of substrates for the target enzymes
2. Development of an assay to detect enzyme activity
3. The use of the developed tools to analyse enzyme function in vitro and in cells

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. The training program will be of a multidisciplinary nature, combining synthetic chemistry with biochemistry and molecular biology techniques. Specifically, the student will receive training in organic synthesis (including carbohydrate synthesis and solid phase peptide synthesis), HPLC purification, and various analytical techniques including LCMS and NMR characterization; and will also develop skills in SDS-PAGE and immunoblotting, affinity purification, cloning, cell culture, protein expression in both bacterial and mammalian systems, enzyme activity assays, and mass spectrometry analysis. Furthermore, the student will have the opportunity to participate in crystallography studies in the laboratory of Prof Davies.

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.

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

Funding Notes

This project is available to students from any country who can fund their own studies. The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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