Abstract
Protein palmitoylation is the post-translational attachment of fatty acids, most commonly palmitate (C16 : 0), onto a cysteine residue of a protein. This reaction is catalysed by a family of integral membrane proteins, the zDHHC protein acyltransferases (PATs), so-called due to the presence of an invariant Asp-His-His-Cys (DHHC) cysteine-rich domain harbouring the catalytic centre of the enzyme. Conserved throughout eukaryotes, the zDHHC PATs are encoded by multigene families and mediate palmitoylation of thousands of protein substrates. In humans, a number of zDHHC proteins are associated with human diseases, including intellectual disability, Huntington's disease, schizophrenia and cancer. Key to understanding the physiological and pathophysiological importance of individual zDHHC proteins is the identification of their protein substrates. Here, we will describe the approaches and challenges in assigning substrates for individual zDHHCs, highlighting key mechanisms that underlie substrate recruitment.
Highlights
Protein fatty acylation refers to the covalent attachment of a fatty acid to a protein
All three motifs are on the cytoplasmic face of the membrane, with the DPG motif shortly preceding the DHHC-cysteine-rich domain (CRD), while the TTxE and the palmitoyltransferase conserved C-terminal (PaCCT) motifs are C-terminal to the DHHC-CRD
An alternative to assaying substrate palmitoylation to identify the candidate protein acyltransferases (PATs) is to examine the consequences of silencing an individual zDHHC protein on the localization of a specific substrate
Summary
Protein fatty acylation refers to the covalent attachment of a fatty acid to a protein. Fatty acids of various lengths and degrees of unsaturation can be attached to a protein via a glycine (N-terminal myristoylation), lysine (εN-fatty acylation), serine (O-fatty acylation) or cysteine (S-fatty acylation) residue [1,2]. Among these modifications, S-fatty acylation is the most prevalent [2,3,4]. This review will focus on common themes in the assignment and recruitment of palmitoylation substrates by the zDHHC PATs. We will first provide an overview of the shared structure and mechanism within this enzyme family, outline approaches to identify substrates for individual zDHHC proteins and discuss the mechanisms that underlie substrate recruitment. For a detailed look at the structure and mechanism of zDHHC-mediated palmitoylation, the reader is referred to [35,36]
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