Protein depalmitoylases

Abstract

Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G protein depalmitoylases, yet later were shown to accept a number of S-palmitoylated protein and phospholipid substrates. Leveraging the development of isoform-selective APT inhibitors, several studies report distinct roles for APT enzymes in growth factor and hormonal signaling. Recent crystal structures of APT1 and APT2 reveal convergent acyl binding channels, suggesting additional factors beyond acyl chain recognition mediate substrate selection. In addition to APT enzymes, the ABHD17 family of hydrolases contributes to the depalmitoylation of Ras-family GTPases and synaptic proteins. Overall, enzymatic depalmitoylation ensures efficient membrane targeting by balancing the palmitoylation cycle, and may play additional roles in signaling, growth, and cell organization. In this review, we provide a perspective on the biochemical, structural, and cellular analysis of protein depalmitoylases, and outline opportunities for future studies of systems-wide analysis of protein depalmitoylation.

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

“…Chemically, the thiol group of the target cysteine residue reacts with the carbonyl carbon of the lipid moiety forming a thioester bond, which is more labile than its oxyester counterpart (Castro 1999). In a biological context, the S-acylation reaction is catalyzed by a family of enzymes named protein S-acyltransferases (PATs) whereas the reverse reaction, deacylation, is catalyzed by the socalled acyl protein thioesterases (APTs) or deacylases (Figure 1(A)) (Tsutsumi et al 2008;Won et al 2018).…”

Stress-induced changes in the S-palmitoylation and S-nitrosylation of synaptic proteins

“…Spalmitoylation modulates multiple aspects of synaptic protein activity, including trafficking, conformational changes, stability, protein-protein interactions, and other PTMs (Fukata et al, 2013, Lussier et al, 2015, Conibear and Davis, 2010. The regulation of S-PALM is mediated by two types of enzymes: (I) protein acyltransferases (PATs) that attach the palmitate group to protein side chains and (II) acyl-protein thioesterases (APTs) that depalmitoylate proteins that hydrolyze thioester bonds (Greaves and Chamberlain, 2011, Salaun et al, 2010, Noritake et al, 2009, Won et al, 2018, De and Sadhukhan, 2018. In addition to enzymatic control, the dynamics of S-PALM are regulated by other protein modifications that occur in the target protein, such as phosphorylation and S-NO (Gauthier-Kemper et al, 2014, Salaun et al, 2010.…”

AMPAR Palmitoylation Tunes Synaptic Strength: Implications for Synaptic Plasticity and Disease

“…These PATs are encoded by the ZDHHC gene family (Fukata et al, 2004). Depalmitoylation, on the other hand, is performed by multiple enzyme classes (acyl-protein thioesterases, palmitoyl-protein thioesterases, and the ␣/␤-hydrolase domain 17 proteins) that collectively make up the depalmitoylases (Won et al, 2018). Palmitoylation increases the hydrophobicity of proteins, generally increasing their association with cellular membranes.…”