Structure and Mechanism of DHHC Protein Acyltransferases

• Published in: Journal of molecular biology 2020-08, Vol.432 (18), p.4983-4998
• Main Authors: Stix, Robyn, Lee, Chul-Jin, Faraldo-Gómez, José D., Banerjee, Anirban
• Format: Article
• Language: English
• Subjects: Acylation; Acyltransferases - chemistry; Acyltransferases - metabolism; Crystallography, X-Ray; fatty acids; Humans; membrane deformation; membrane enzyme; Models, Molecular; Protein Domains; Protein Processing, Post-Translational; S-acylation; structure
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2020.05.023

S-acylation, whereby a fatty acid chain is covalently linked to a cysteine residue by a thioester linkage, is the most prevalent kind of lipid modification of proteins. Thousands of proteins are targets of this post-translational modification, which is catalyzed by a family of eukaryotic integral membrane enzymes known as DHHC protein acyltransferases (DHHC-PATs). Our knowledge of the repertoire of S-acylated proteins has been rapidly expanding owing to development of the chemoproteomic techniques. There has also been an increasing number of reports in the literature documenting the importance of S-acylation in human physiology and disease. Recently, the first atomic structures of two different DHHC-PATs were determined using X-ray crystallography. This review will focus on the insights gained into the molecular mechanism of DHHC-PATs from these structures and highlight representative data from the biochemical literature that they help explain. [Display omitted] •Protein S-acylation is one of the most abundant forms of protein lipidation.•Members of the DHHC family of integral membrane enzymes catalyze protein S-acylation in eukaryotes.•High-resolution structures of two members of the family revealed a tremendous amount of information about organization and mechanism of DHHC enzymes.•Atomistic molecular dynamics simulation revealed DHHC enzymes deform the membrane to facilitate catalysis.