Molecular basis of fatty acid selectivity in the zDHHC family of S-acyltransferases revealed by click chemistry

Jennifer Greaves, Kevin R. Munro, Stuart C. Davidson, Matthieu Riviere, Justyna Wojno, Terry K. Smith, Nicholas C.O. Tomkinson, Luke H. Chamberlain

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)
60 Downloads (Pure)


S-acylation is a major posttranslational modification, catalyzed by the zinc finger DHHC domain containing (zDHHC) enzyme family. S-acylated proteins can be modified by different fatty acids; however, very little is known about how zDHHC enzymes contribute to acyl chain heterogeneity. Here, we used fatty acid-azide/alkyne labeling of mammalian cells, showing their transformation into acyl-CoAs and subsequent click chemistry-based detection, to demonstrate that zDHHC enzymes have marked differences in their fatty acid selectivity. This difference in selectivity was apparent even for highly related enzymes, such as zDHHC3 and zDHHC7, which displayed a marked difference in their ability to use C18:0 acyl-CoA as a substrate. Furthermore, we identified isoleucine-182 in transmembrane domain 3 of zDHHC3 as a key determinant in limiting the use of longer chain acyl-CoAs by this enzyme. This study uncovered differences in the fatty acid selectivity profiles of cellular zDHHC enzymes and mapped molecular determinants governing this selectivity.

Original languageEnglish
Pages (from-to)E1365-E1374
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
Early online date6 Feb 2017
Publication statusPublished - 21 Feb 2017
Externally publishedYes

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  • Acyl CoA
  • Click chemistry
  • Palmitoylation
  • S-acylation
  • zDHHC enzyme

ASJC Scopus subject areas

  • General


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