Foreword: Protein acylation and microdomains in membrane function

Protein acylation, the covalent attachment of long chain fatty acids to proteins, has been known for about 30 years but is currently enjoying a heyday, which is highlighted in this thematic issue. S-acylation (also called thioacylation or palmitoylation), involving thioester linkage of the fatty acid to protein cysteine residues, is of particular interest because it has the unique property among protein lipid modifications that it is reversible in vivo under physiological conditions. Several major recent advances have contributed to the explosion of studies in this field: the development of new assays, the identification of enzymes catalyzing acylation and deacylation, and increased understanding of the functions of protein acylation. The chapters below, by leaders in all aspects of the area, provide a snapshot of the current state of the art in this burgeoning field. The first paper by Draper and Smith summarizes new assays for protein acyltransferases which have increased the speed and sensitivity of detecting the modification and substantially superceded the need for radioactive palmitate incorporation, although this still has its place as the gold standard method. The field of protein acylation has also suffered from the lack of specific and potent inhibitors, previously relying on rather unsatisfactory compounds such as 2-bromopalmitate and cerulenin that have multiple side effects. Given the great potential for therapeutic intervention targeted at protein acylation in several diseases, these inhibitors could form the basis for useful drugs in future; Draper and Smith present recent studies on new lead compounds that specifically target protein S-acyltransferases (PATs). A massive boost to the field was given in the early 2000s when, after years of unsuccessful attempts by many groups, DHHC-CRD family PATs were identified by Deschenes’ and Linder’s groups first in yeast [1] and subsequently in vertebrates. There are currently seven yeast DHHC-CRD PATs known and 23 in man, which show both partial redundancy and specificity in their substrate repertoire. This family of enzymes is reviewed by Planey and Zacharias who also highlight novel acylation assays and how they are being used to study the palmitoylproteome of different organisms and cell types. For S-acylation to be reversible, protein acylthioesterases are required. This small and understudied family of enzymes is reviewed by Zeidman, Jackson and Magee in the third paper. In contrast to the great diversity of DHHC PATs, only two protein acylthioesterases have definitively been shown to deacylate intracellular proteins under conditions where they could play a role in physiological regulation of the acylation-deacylation cycle. Does this mean that all the specificity in these cycles comes from the PATs and the thioesterases are simply broad specificity enzymes that catalyse deacylation of a wide range of substrates? Too little is currently known about these enzymes to answer this question, but an intriguing possibility springs to mind from the observation of Zeidman et al. that these proteins, which are inherently hydrophilic in nature, show a substantial fraction associated with cellular membranes. One wonders whether they could associate with specific subcellular membranes through dedicated adaptor and targeting molecules, in an analogous fashion to the targeting of protein kinases A and C by A kinase anchoring proteins (AKAPs) and receptors for activated C kinase (RACKs) respectively [2,3]. The next paper entitled ‘Palmitoylation cycles and regulation of protein function’ by Kanaani and Baekkeskov elegantly illustrates how acylation-deacylation cycles can modulate protein localization and function. Many acylated proteins are inherently soluble based on their primary sequence and their