PROTEIN S-ACYLATION IN HEALTH AND DISEASE

S-acylation (aka palmitoylation), the reversible attachment of fatty acids onto cysteine residues, regulates a diverse array of proteins and impacts fundamental cellular processes such as signalling, membrane traffic, communication, and growth and division. Defects in S-acylation are linked with cancer, diabetes, and CNS disorders such as intellectual disability, epilepsy, Huntington’s disease and neuronal ceroid lipofuscinosis. In addition, S-acylation is required for infection and virulence of some viruses and parasites. As a result, there is growing interest in the therapeutic potential of targeting the S-acylation machinery, with a major goal being the development of isoform-selective inhibitors against the 23 zDHHC S-acyltransferase enzymes.

OUR RESEARCH

The research that we are undertaking aims to unravel the multitude of functions that S-acylation plays in cellular pathways, in particular, signalling and membrane traffic. In addition, we aim to understand how defects in S-acylation contribute to disorders such as intellectual disability, epilepsy, neurodegeneration, cancer and diabetes. Through this work we hope to identify novel drug targets and new drug treatments for these conditions. We use a wide range of techniques including chemical biology (click chemistry), confocal microscopy, proteomics, and behavioural analyses.

Our research falls into two major programmes:

1. S-acylation and cell function in health and disease

(i) How does dynamic S-acylation of key signalling and trafficking proteins regulate cell pathways and how does disruption of this process cause disease?

(ii) What are the molecular effects of S-acylation that underlie protein regulation?

(iii) Does acyl chain heterogeneity provide functionally distinct pools of the same protein?

2. The zDHHC family of S-acyltransferases

(i) What are the substrate networks of individual zDHHC enzymes, and how is enzyme-substrate specificity encoded?

(ii) How do zDHHC enzymes select specific acyl-CoAs from a mixed population?

(iii) How do multiple zDHHC enzyme isoforms coordinate protein S-acylation at the level of a single intracellular organelle?

(iv) What are the cellular and molecular changes that underlie disease phenotypes caused by ZDHHC mutations?

(v) Can we develop isoform-selective chemical modulators of the zDHHC enzyme family?

RESEARCH OPPORTUNITIES

We would be delighted to hear from post-doctoral researchers interested in developing fellowhsip proposals that can be hosted in our lab. We can offer support and mentorship for fellowship applications.

We are also happy to speak with prospective PhD students who have secured funding.

All enquiries can be directed to [email protected]