EW Tate
Global profiling and inhibition of protein lipidation in vector and host stages of the sleeping sickness parasite Trypanosoma brucei
Tate, EW; Wright, MH; Paape, D; Price, H; Smith, DF
Abstract
The enzyme N-myristoyltransferase (NMT) catalyzes the essential fatty acylation of substrate proteins with myristic acid in eukaryotes and is a validated drug target in the parasite Trypanosoma brucei, the causative agent of African trypanosomiasis (sleeping sickness). N-Myristoylation typically mediates membrane localization of proteins and is essential to the function of many. However, only a handful of proteins are experimentally validated as N-myristoylated in T. brucei. Here, we perform metabolic labeling with an alkyne-tagged myristic acid analogue, enabling the capture of lipidated proteins in insect and host life stages of T. brucei. We further compare this with a longer chain palmitate analogue to explore the chain length-specific incorporation of fatty acids into proteins. Finally, we combine the alkynyl-myristate analogue with NMT inhibitors and quantitative chemical proteomics to globally define N-myristoylated proteins in the clinically relevant bloodstream form parasites. This analysis reveals five ARF family small GTPases, calpain-like proteins, phosphatases, and many uncharacterized proteins as substrates of NMT in the parasite, providing a global view of the scope of this important protein modification and further evidence for the crucial and pleiotropic role of NMT in the cell.
Journal Article Type | Article |
---|---|
Acceptance Date | Apr 29, 2016 |
Publication Date | Apr 29, 2016 |
Publicly Available Date | Mar 29, 2024 |
Journal | ACS Infectious Diseases |
Publisher | American Chemical Society |
Peer Reviewed | Peer Reviewed |
Volume | 2 |
Issue | 6 |
Pages | 427-441 |
DOI | https://doi.org/10.1021/acsinfecdis.6b00034 |
Keywords | human African trypanosomiasis, N-myristoylation, chemical proteomics, click chemistry, protein lipidation, target validation |
Publisher URL | http://dx.doi.org/10.1021/acsinfecdis.6b00034 |
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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