Background: S-Acylation, a protein lipidation process that is essential for neuronal functions, is catalyzed by zDHHC S-acyltransferases.Results: The ankyrin repeat (AR) domains of zDHHC17 and zDHHC13 recognize a novel unstructured peptide sequence in several unrelated proteins.Conclusion: Several proteins have independently acquired similar short peptide sequences for zDHHC17/13 binding.Significance: This is the first study to identify a motif recognized by AR-containing S-acyltransferases.

The molecular machinery that catalyzes S-acylation reactions at the Golgi comprises zDHHC enzymes with major differences in substrate affinity and S-acylation activity. It is proposed that the coexistence of these two groups of enzymes in cells is important to allow the Golgi S-acylation machinery to modify a wide and diverse set of substrates.

The discovery of the zDHHC family of S-acyltransferase enzymes has been one of the major breakthroughs in the S-acylation field. Now, more than a decade since their discovery, major questions centre on profiling the substrates of individual zDHHC enzymes (there are 24 ZDHHC genes and several hundred S-acylated proteins), defining the mechanisms of enzyme-substrate specificity and unravelling the importance of this enzyme family for cellular physiology and pathology.

Palmitoylation, the attachment of palmitate and other fatty acids on to cysteine residues, is a common post-translational modification of both integral and peripheral membrane proteins. Dynamic palmitoylation controls the intracellular distribution of peripheral membrane proteins by regulating membrane-cytosol exchange and/or by modifying the flux of the proteins through vesicular transport systems.