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

我们体内的细胞含有多种不同的蛋白质，这些蛋白质协调和驱动特定的途径，如细胞生长和分裂。这些蛋白质受到严格的调控模式，以确保它们能够在需要时执行其特定功能。蛋白质调节的一个突出机制是通过化学修饰，将各种不同的分子添加到影响其活性的蛋白质中。一种受到越来越多关注的修饰是“S-酰化”，即脂肪酸与蛋白质的连接，其由二十四种“DHHC”酶家族催化。DHHC酶的功能障碍与许多重要的疾病有关，包括糖尿病、亨廷顿氏病、精神分裂症、智力残疾和癌症。添加到S-酰化蛋白质中的脂肪酸可以是多种多样的，并且不同的脂肪酸可能以不同的方式影响蛋白质。尽管如此，我们目前对添加到单个S-酰化蛋白质中的脂肪酸的化学特性的机制以及脂肪酸特性如何影响蛋白质功能知之甚少。因此，本研究的目的是促进这方面的S-酰化的了解甚少的重大进展。为此，我们召集了化学和生物学专家，目的是使用新型化学探针来确定：（a）如果不同的DHHC酶优先将不同类型的脂肪酸添加到S-酰化蛋白质上，（B）DHHC酶的哪些特征是它们的脂肪酸特异性的基础，以及（c）不同的脂肪酸如何影响蛋白质在细胞不同区域的定位及其在特定细胞途径中的功能。除了阐明细胞生物学的一个重要但知之甚少的方面外，这项研究还可能突出设计DHHC酶的选择性调节剂以治疗一系列临床疾病的新策略。

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.