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Nat Chem Biol. 2017 Mar;13(3):333-338. doi: 10.1038/nchembio.2284. Epub 2017 Jan 23.

Akt3 is a privileged first responder in isozyme-specific electrophile response.

Author information

1
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
2
Proteomics and Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, USA.
3
Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA.

Abstract

Isozyme-specific post-translational regulation fine tunes signaling events. However, redundancy in sequence or activity renders links between isozyme-specific modifications and downstream functions uncertain. Methods to study this phenomenon are underdeveloped. Here we use a redox-targeting screen to reveal that Akt3 is a first-responding isozyme sensing native electrophilic lipids. Electrophile modification of Akt3 modulated downstream pathway responses in cells and Danio rerio (zebrafish) and markedly differed from Akt2-specific oxidative regulation. Digest MS sequencing identified Akt3 C119 as the privileged cysteine that senses 4-hydroxynonenal. A C119S Akt3 mutant was hypomorphic for all downstream phenotypes shown by wild-type Akt3. This study documents isozyme-specific and chemical redox signal-personalized physiological responses.

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PMID:
28114274
PMCID:
PMC5586141
DOI:
10.1038/nchembio.2284
[Indexed for MEDLINE]
Free PMC Article

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