Molecular basis of fatty acid selectivity in the zDHHC family of S-acyltransferases revealed by click chemistry
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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.
Greaves , J , Munro , K R , Davidson , S C , Riviere , M , Wojno , J , Smith , T K , Tomkinson , N C O & Chamberlain , L H 2017 , ' Molecular basis of fatty acid selectivity in the zDHHC family of S-acyltransferases revealed by click chemistry ' Proceedings of the National Academy of Sciences of the United States of America , vol 114 , no. 8 , pp. E1365-E1374 . DOI: 10.1073/pnas.1612254114
Proceedings of the National Academy of Sciences of the United States of America
© 2017, the Author(s). This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.pnas.org / https://doi.org/10.1073/pnas.1612254114
This work was funded by Biotechnology and Biological Sciences Research Council Grant BB/L022087/1 (to T.K.S., N.C.O.T., and L.H.C.) and Wellcome Trust Grant 093228 (to T.K.S.).
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