Attachment of lipids to proteins is one of the most abundant and physiologically important forms of protein modification. Protein S-acylation, commonly known as protein palmitoylation, is by far the most pervasive form of protein lipidation with thousands of protein targets acted on by 23 members of transmembrane enzymes belonging to the zDHHC family. Protein S-acylation intersects with almost all areas of cellular physiology and has been linked to numerous diseases including various forms of neurodegenerative disease, cancer and cardiac disease. Yet, the detailed structural chemical understanding of how zDHHC enzymes acquire long chain fatty acyl CoA, and transfer them onto their substrates has remained unknown till recently. In this talk I will present our work in elucidating the molecular mechanism of these enzymes using a multipronged approach combining structural biology, chemical biology, and biophysics. Through these, we have established the first detailed view into the chemical and cellular mechanism of zDHHC enzymes. Our work opens up ways to further understanding of this critical area of protein modification and membrane enzymology that will lead to both advancements of fundamental understanding of protein S-acylation, as well as discovery of novel therapeutic strategies to target them for human diseases.
Prof Anirban Banerjee (Sun,) studied this question.