Acyl-protein thioesterase
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 Crystal structure of human APT1, PDB code 1fj2. Alpha helices are in red, beta strands in gold, catalytic site residues in black. The 2 different monomers of the dimer are shaded in green and brown. | |||||||||
| Identifiers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Symbol | Acyl-protein thioesterases (APTs) | ||||||||
| Pfam | PF02230 | ||||||||
| InterPro | IPR029058 | ||||||||
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Acyl-protein thioesterases are enzymes that cleave off lipid modifications on proteins, located on the sulfur atom of cysteine residues linked via a thioester bond.[1] Acyl-protein thioesterases are part of the α/β hydrolase superfamily of proteins and have a conserved catalytic triad.[2] For that reason, acyl-protein thioesterases are also able to hydrolyze oxygen-linked ester bonds.
Acyl-protein thioesterases are involved in the depalmitoylation of proteins, meaning they cleave off palmitoyl modifications on proteins' cysteine residues. Cellular targets include trimeric G-alpha proteins,[3] ion channels[4] and GAP-43.[5] Moreover, human acyl-protein thioesterases 1 and 2 have been identified as major components in controlling the palmitoylation cycle of the oncogene Ras.[6][7] Depalmitoylation of Ras by acyl-protein thioesterases potentially reduces Ras' affinity to endomembranes, allowing it to be palmitoylated again at the Golgi apparatus and to be directed to the plasma membrane. Acyl-protein thioesterases, therefore, are thought to correct potential mislocalization of Ras.
Known enzymes
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Currently fully validated human acyl-protein thioesterases are APT1[8] and APT2[9] which share 66% sequence homology.[10] Additionally there are a handful of putative acyl-protein thioesterases reported, including the ABHD17 enzyme family.[11][12] In the lysosome, PPT1 of the palmitoyl protein thioesterase family has similar enzymatic activity as acyl-protein thioesterases.
Structure
Acyl-protein thioesterases feature 3 major structural components that determine protein function and substrate processing: 1. A conserved, classical catalytic triad to break ester and thioester bonds;[2] 2. A long hydrophobic substrate tunnel to accommodate the palmitoyl moiety, as identified in the crystal structures of human acyl-protein thioesterase 1,[2] human acyl-protein thioesterase 2[13] and Zea mays acyl-protein thioesterase 2;[14] 3. A lid-loop that covers the catalytic site, is highly flexible and is a main factor determining the enzyme's product release rate.[14]
