Fatty Acid Specificity in the DHHC Family of S-Acyltransferases: From Mechanisms to Functional Outcomes

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The cells in our body contain a diverse array of different proteins that coordinate and drive specific pathways, such as cell growth and division. These proteins are subjected to strict modes of regulation to ensure that they are able to perform their specific functions as and when required. One prominent mechanism of protein regulation is via chemical modification and a variety of different molecules are added to proteins that affect their activity. One modification that is receiving increasing interest is "S-acylation", the attachment of fatty acids onto proteins, which is catalysed by a family of twenty-four "DHHC" enzymes. Dysfunction of DHHC enzymes has been linked with many important disorders, including diabetes, Huntington's disease, schizophrenia, intellectual disability and cancer.The fatty acids that are added to S-acylated proteins can be diverse and it is likely that different fatty acids affect proteins in different ways. Despite this, we currently know very little about the mechanisms that specify the chemical identity of fatty acids added to individual S-acylated proteins, and how fatty acid identity impacts protein function. Therefore the aim of this research is to promote a major advance in this poorly understood aspect of S-acylation. To do this, we have brought together experts in Chemistry and Biology with the goal of using novel chemical probes to determine: (a) if different DHHC enzymes preferentially add distinct types of fatty acids onto S-acylated proteins, (b) what features of DHHC enzymes underlie their fatty acid specificity, and (c) how different fatty acids affect the localisation of proteins to different regions of the cell and their function in specific cellular pathways. In addition to shedding light on an important but poorly understood aspect of cell biology, this research may also highlight new strategies to design selective modulators of DHHC enzymes to treat a range of clinical conditions.