6qgs
Crystal structure of APT1 bound to palmitic acid.
Structural highlights
FunctionLYPA1_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] Publication Abstract from PubMedMany biochemical reactions require controlled recruitment of proteins to membranes. This is largely regulated by posttranslational modifications. A frequent one is S-acylation, which consists of the addition of acyl chains and can be reversed by poorly understood acyl protein thioesterases (APTs). Using a panel of computational and experimental approaches, we dissect the mode of action of the major cellular thioesterase APT2 (LYPLA2). We show that soluble APT2 is vulnerable to proteasomal degradation, from which membrane binding protects it. Interaction with membranes requires three consecutive steps: electrostatic attraction, insertion of a hydrophobic loop and S-acylation by the palmitoyltransferases ZDHHC3 or ZDHHC7. Once bound, APT2 is predicted to deform the lipid bilayer to extract the acyl chain bound to its substrate and capture it in a hydrophobic pocket to allow hydrolysis. This molecular understanding of APT2 paves the way to understand the dynamics of APT2-mediated deacylation of substrates throughout the endomembrane system. Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains.,Abrami L, Audagnotto M, Ho S, Marcaida MJ, Mesquita FS, Anwar MU, Sandoz PA, Fonti G, Pojer F, Dal Peraro M, van der Goot FG Nat Chem Biol. 2021 Apr;17(4):438-447. doi: 10.1038/s41589-021-00753-2. Epub 2021, Mar 11. PMID:33707782[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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