Title : A palmitoyl transferase chemical-genetic system to map ZDHHC-specific S-acylation - Ocasio_2024_Nat.Biotechnol__ |
Author(s) : Ocasio CA , Baggelaar MP , Sipthorp J , Losada de la Lastra A , Tavares M , Volaric J , Soudy C , Storck EM , Houghton JW , Palma-Duran SA , MacRae JI , Tomic G , Carr L , Downward J , Eggert US , Tate EW |
Ref : Nat Biotechnol , : , 2024 |
Abstract :
The 23 human zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases catalyze long-chain S-acylation at cysteine residues across an extensive network of hundreds of proteins important for normal physiology or dysregulated in disease. Here we present a technology to directly map the protein substrates of a specific ZDHHC at the whole-proteome level, in intact cells. Structure-guided engineering of paired ZDHHC 'hole' mutants and 'bumped' chemically tagged fatty acid probes enabled probe transfer to specific protein substrates with excellent selectivity over wild-type ZDHHCs. Chemical-genetic systems were exemplified for five human ZDHHCs (3, 7, 11, 15 and 20) and applied to generate de novo ZDHHC substrate profiles, identifying >300 substrates and S-acylation sites for new functionally diverse proteins across multiple cell lines. We expect that this platform will elucidate S-acylation biology for a wide range of models and organisms. |
PubMedSearch : Ocasio_2024_Nat.Biotechnol__ |
PubMedID: 38191663 |
Ocasio CA, Baggelaar MP, Sipthorp J, Losada de la Lastra A, Tavares M, Volaric J, Soudy C, Storck EM, Houghton JW, Palma-Duran SA, MacRae JI, Tomic G, Carr L, Downward J, Eggert US, Tate EW (2024)
A palmitoyl transferase chemical-genetic system to map ZDHHC-specific S-acylation
Nat Biotechnol
:
Ocasio CA, Baggelaar MP, Sipthorp J, Losada de la Lastra A, Tavares M, Volaric J, Soudy C, Storck EM, Houghton JW, Palma-Duran SA, MacRae JI, Tomic G, Carr L, Downward J, Eggert US, Tate EW (2024)
Nat Biotechnol
: