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*EASTBIO* Illuminating the dark proteome for therapeutic gain – direct detection and discovery of S-acylated proteins

  • Full or part time
    Prof T K Smith
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

BBSRC Thematic Group: Frontier Bioscience
S-acylation is a fatty acid based post-translational modification of proteins and it has been suggested that ~50% of eukaryotic membrane proteins are modified by S-acylation. This makes it a major factor in how membrane associated processes occur and are regulated. S-acylation is reversible, in a similar manner to phosphorylation or ubiquitination, and is now emerging as a key regulator of cellular function. In humans, defective S-acylation is known to be associated with many cancers, required for nerve growth and function and cardiac ion channel regulation, while in protozoan parasites such as Trypanosomes and Apicomplexa S-acylation is critical for infectivity and completing their lifecycle.

A major barrier to progress is the identification of S-acylated proteins in any eukaryote, and in particular identification of proteins that change S-acylation state in response to a stimulus or during a life/cell-cycle. Due to the highly hydrophobic nature of S-acyl groups S-acylated peptides from proteins are not detectable using standard proteomic methods. Current proteomic approaches to identify S-acylated proteins are either indirect or use metabolic labelling and only capture a subset of S-acylated proteins. In addition, these methods frequently cannot inform where the site of modification is within a protein. All of these limitations mean that much of the S-acylated proteome, and particularly its dynamics, has yet to be characterised and explored.

We will also focus on parasites within the phylae Kinetoplastidae and Apicomplexa, that causes high morbidity and mortality in domestic animals with huge direct and indirect effects on food and nutritional security and large economic losses per year. These include Trypanosoma brucei brucei the causative agents of Nagana (African Animal Trypanosomiasis, AAT) and Sarcocystis neurona causing sarcocystosis, one of the most common parasites in domestic animals in many parts of the world.

The recent validation of a drug targeting Trypanosomal N-myristoyl transferase-I indicates that fatty acid based post-translational modifications are suitable therapeutic targets. Inhibiting S-acylation in Trypanosomes represents a viable route to therapeutic development, thus we need to have a robust understanding of S-acyl proteome dynamics within the parasite during each of its life stages to full asses its impact, allowing us to extrapolate to other important pathogens and diseases.

The aim of this project is therefore three-fold: 1) Initial development of novel extraction and separation methods based upon recent developments in the field, allowing isolation of S-acylated proteins/peptides from complex cellular proteomes and identify them by mass-spectrometry. 2) Validation, optimization and benchmarking of the approach using well studied mammalian HEK-293 cells. 3) Subsequently you will use your methods to define the trypanosome S-acyl proteome and how it changes during different life/cell-cycle changes as well as in response to exogenous stimuli and/or current/potential therapeutic drug treatments. The sarcocystis S-acyl proteome will also be investigated similarly if time allows.

Funding Notes

This project is eligible for the EASTBIO Doctoral Training Partnership: View Website

This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

Apply by 5.00 pm on 5 January 2020 following the instructions on how to apply at: View Website

Please also upload the EASTBO Application Form as an additional document to the University of St Andrews online Application.

Informal inquiries to the primary supervisor are very strongly encouraged.

References

General S-acylation review: Zaballa and van der Goot (2018) Crit Rev Biochem Mol Biol. 53(4):420-451. doi: 10.1080/10409238.2018.1488804.

Proof of principle proteomic detection of S-acylated peptides: Yi et al (2013) Analytical Chemistry 85(24):11952-9. doi: 10.1021/ac402850s.

Protein fatty acid modifications as drug targets: Frearson J. A et al (2010) Nature, 464(7289):728-32. doi: 10.1038/nature08893.

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

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

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