6qgo

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Crystal structure of APT1 S119A mutant bound to palmitic acid.Crystal structure of APT1 S119A mutant bound to palmitic acid.

Structural highlights

6qgo is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.599Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Many 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 Also

References

  1. 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
  2. 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. Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains. Nat Chem Biol. 2021 Apr;17(4):438-447. doi: 10.1038/s41589-021-00753-2. Epub 2021, Mar 11. PMID:33707782 doi:http://dx.doi.org/10.1038/s41589-021-00753-2

6qgo, resolution 2.60Å

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