Structural highlights
Function
[LYPA1_HUMAN] Hydrolyzes fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS. Has depalmitoylating activity and also low lysophospholipase activity.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Many proteins undergo posttranslational modifications involving covalent attachment of lipid groups. Among them is palmitoylation, a dynamic, reversible process that affects trimeric G proteins and Ras and constitutes a regulatory mechanism for signal transduction pathways. Recently, an acylhydrolase previously identified as lysophospholipase has been shown to function as an acyl protein thioesterase, which catalyzes depalmitoylation of Galpha proteins as well as Ras. Its amino acid sequence suggested that the protein is evolutionarily related to neutral lipases and other thioesterases, but direct structural information was not available. RESULTS: We have solved the crystal structure of the human putative Galpha-regulatory protein acyl thioesterase (hAPT1) with a single data set collected from a crystal containing the wild-type protein. The phases were calculated to 1.8 A resolution based on anomalous scattering from Br(-) ions introduced in the cryoprotectant solution in which the crystal was soaked for 20 s. The model was refined against data extending to a resolution of 1.5 A to an R factor of 18.6%. The enzyme is a member of the ubiquitous alpha/beta hydrolase family, which includes other acylhydrolases such as the palmitoyl protein thioesterase (PPT1). CONCLUSIONS: The human APT1 is closely related to a previously described carboxylesterase from Pseudomonas fluorescens. The active site contains a catalytic triad of Ser-114, His-203, and Asp-169. Like carboxylesterase, hAPT1 appears to be dimeric, although the mutual disposition of molecules in the two dimers differs. Unlike carboxylesterase, the substrate binding pocket and the active site of hAPT1 are occluded by the dimer interface, suggesting that the enzyme must dissociate upon interaction with substrate.
Crystal structure of the human acyl protein thioesterase I from a single X-ray data set to 1.5 A.,Devedjiev Y, Dauter Z, Kuznetsov SR, Jones TL, Derewenda ZS Structure. 2000 Nov 15;8(11):1137-46. PMID:11080636[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dekker FJ, Rocks O, Vartak N, Menninger S, Hedberg C, Balamurugan R, Wetzel S, Renner S, Gerauer M, Scholermann B, Rusch M, Kramer JW, Rauh D, Coates GW, Brunsveld L, Bastiaens PI, Waldmann H. Small-molecule inhibition of APT1 affects Ras localization and signaling. Nat Chem Biol. 2010 Jun;6(6):449-56. doi: 10.1038/nchembio.362. Epub 2010 Apr 25. PMID:20418879 doi:http://dx.doi.org/10.1038/nchembio.362
- ↑ Devedjiev Y, Dauter Z, Kuznetsov SR, Jones TL, Derewenda ZS. Crystal structure of the human acyl protein thioesterase I from a single X-ray data set to 1.5 A. Structure. 2000 Nov 15;8(11):1137-46. PMID:11080636
