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Using chemical biology to understand the importance of glycans in neurotrophism

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  • Full or part time
    Dr N McDonald
    Dr B Schumann
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This 4-year PhD studentship is offered in Dr Neil McDonald’s Group based at the Francis Crick Institute (the Crick) & Dr Ben Schumann’s Group based at Imperial College London.

All living cells are covered by a layer of carbohydrates (glycans) that are covalently attached to proteins or lipids. Consequently, all physiological processes that take place on the cell surface are potentially modulated by glycosylation. In fact, glycans have been found to impact signalling, immune recognition, cell-cell and cell-matrix interactions, to name but a few. As glycans are secondary gene products, their biosynthesis is not template-directed. Traditional methods of cell and molecular biology are thus restricted to manipulating the expression of glycosyltransferases (GTs) and other glycan biosynthesis enzymes. More than 250 GTs are expressed in humans in a stage- and tissue-specific manner and use one of several sugar donors, thereby tremendously increasing the complexity of glycans over other posttranslational modifications. Understanding a) how glycan complexity is manifested and b) how this complexity impacts biology remain the most important challenges to date.

Modern biology and biochemistry have brought about methods to characterise and manipulate biomolecules in great depth. The Chemical Glycobiology Laboratory led by Ben Schumann (The Francis Crick Institute, Imperial College London) complements these methods with approaches of synthetic and analytical chemistry to study glycans in biological contexts. Chemical tools are of particular relevance to characterising and manipulating glycans, and are transforming our understanding of glycobiology. We develop these “precision tools”, establish them in the living cell and use sophisticated methods of proteomics and genome manipulation to tackle complex biological problems.

With the advent of increasingly sensitive structure determination methods, the relevance of glycans to fine-tuning protein-protein interactions is becoming clear. The Signalling and Structural Biology Laboratory led by Neil McDonald (the Francis Crick Institute) has a long-standing interest in the GDNF neurotrophic factor signalling both in neuronal trophic survival and synapse formation. Recent evidence suggests that multiple cell surface components in GDNF signalling are directly modified by glycans influencing the affinity of their molecular interactions. However, the interplay and functional importance of such glycans is not well understood and will be explored by the student.

The student will develop methods to characterise the glycans that are involved in these protein complexes with Ben Schumann, apply the methods to biological model systems and determine structures of relevant molecular complexes bearing glycans with Neil McDonald.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2019 and will register for their PhD at Imperial College London.

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.Additional eligibility criteria apply to this position: applicants to this position will be expected to hold either a 4-year MSci degree (at 2.1 level or higher), or a 3-year undergraduate degree plus a Masters (MSc, MRes, etc.) degree.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) MARCH 19 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Additional eligibility criteria apply to this position: applicants to this position will be expected to hold either a 4-year MSci degree (at 2.1 level or higher), or a 3-year undergraduate degree plus a Masters (MSc, MRes, etc.) degree.

Non-EU applicants are not eligible for the funding for this project.

References

1. Varki, A. (2017)

Biological roles of glycans.

Glycobiology 27: 3-49. PubMed abstract

2. Gilormini, P. A., Batt, A. R., Pratt, M. R. and Biot, C. (2018)

Asking more from metabolic oligosaccharide engineering.

Chemical Science 9: 7585-7595. PubMed abstract

3. Zhang, P., Lu, H., Peixoto, R. T., Pines, M. K., Ge, Y., Oku, S., . . . Craig, A. M. (2018)

Heparan sulfate organizes neuronal synapses through neurexin partnerships.

Cell 174: 1450-1464 e1423. PubMed abstract

4. Goodman, K. M., Kjær, S., Beuron, F., Knowles, P. P., Nawrotek, A., Burns, E. M., . . . McDonald, N. Q. (2014)

RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.

Cell Reports 8: 1894-1904. PubMed abstract



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