Mechanism and function of DHHC S‐Acyltransferases

Protein S‐palmitoylation is a reversible posttranslational modification of proteins with fatty acids. In the last five years, improved proteomic methods have increased the number of proteins identified as substrates for palmitoylation from tens to hundreds. Palmitoylation regulates protein membrane interactions, activity, trafficking, and stability and can be constitutive or regulated by signaling inputs. A family of protein acyltransferases or PATs is responsible for modifying proteins with palmitate or other long‐chain fatty acids on the cytoplasmic face of cellular membranes. The signature feature is a DHHC (Asp‐His‐His‐Cys)‐ cysteine rich domain that is the catalytic center of the enzyme. My presentation will focus on what we have learned about enzyme mechanism, regulation, and the determinants of substrate specificity. There are twenty‐three members of the DHHC family in humans. Their biomedical importance is underscored by associations with intellectual disability, Huntington's Disease, and cancer in humans, raising the possibility of DHHC proteins as targets for therapeutic intervention.