Chamberlain Lab

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S-acylation (also known as palmitoylation) is a post-translational modification (PTM) involving the reversible attachment of fatty acids onto cysteine residues of cellular proteins. Such modification increases the (local or global) hydrophobicity of proteins, and hence their affinity for certain membrane compartments. As a result, their membrane interactions, stability, micro-localisation within membranes and intra-cellular sorting can be greatly affected. S-acylation has been identified on a wide variety of signalling and structural proteins, and affects key physiological processes, including synaptic activity and plasticity, endocrine communication, immune function, cell growth and cell differentiation. Defects in palmitoylation have been linked to major human disorders, such as schizophrenia, intellectual disability, Huntington’s disease and cancer. The recent discovery of a family of twenty-four “zDHHC” S-acyltransferases, which collectively mediate S-acylation of the vast majority of cellular proteins, was a major breakthrough in the field. However, to develop a rational framework to exploit the potential of S-acylation as a new therapeutic target, fundamental questions about the zDHHC family need to be addressed.

 

Although S-acylation is an essential PTM linked to a variety of important diseases, our understanding of how this process is regulated, its physiological relevance, and how dysfunction causes disease is very much in its infancy.  Even with the identification of the zDHHC family in the last decade, whether the primary function of these proteins is mediated via S-acyltransferase activity or other non-canonical activities is not known. Furthermore, our knowledge of zDHHC enzyme function and role is limited due to a number of reasons including: the difficulty in predicting S-acylation sites, the sparse information about zDHHC substrate specificity and regulation, the inadequate knowledge of zDHHC enzyme physiological importance, and the lack of specific tools for manipulating zDHHC function.

 

Our research is investigating the following key areas:

 

  •           Mechanisms that control zDHHC-substrate interaction specificity
  •           Novel modes of regulation of zDHHC enzymes
  •           The physiological importance of zDHHC function and the pathophysiological consequences of dysregulation
  •           Target validation of zDHHC enzymes in disease
  •            Identification of new and selective modulators of zDHHC activity
  •           The functional outcomes of protein S-acylation

Past/Present Sponsors

MRC 

 Wellcome Trust

Diabetes UK

BBSRC

SULSA  

Palmitoylation

Palmitoylation is the most prominent type of S-acylation and involves the covalent and reversible attachment of a 16 carbon saturated fatty acid (palmitic acid) to cysteines of target proteins.