The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators

Rong Gui Hu, Jun Sheng, Xin Qi, Zhenming Xu, Terry T. Takahashi, Alexander Varshavsky

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201 Scopus citations

Abstract

The conjugation of arginine to proteins is a part of the N-end rule pathway of protein degradation. Three amino (N)-terminal residues - aspartate, glutamate and cysteine - are arginylated by ATE1-encoded arginyl-transferases. Here we report that oxidation of N-terminal cysteine is essential for its arginylation. The in vivo oxidation of N-terminal cysteine, before its arginylation, is shown to require nitric oxide. We reconstituted this process in vitro as well. The levels of regulatory proteins bearing N-terminal cysteine, such as RGS4, RGS5 and RGS16, are greatly increased in mouse ATE1-/- embryos, which lack arginylation. Stabilization of these proteins, the first physiological substrates of mammalian N-end rule pathway, may underlie cardiovascular defects in ATE1-/- embryos. Our findings identify the N-end rule pathway as a new nitric oxide sensor that functions through its ability to destroy specific regulatory proteins bearing N-terminal cysteine, at rates controlled by nitric oxide and apparently by oxygen as well.

Original languageEnglish (US)
Pages (from-to)981-986
Number of pages6
JournalNature
Volume437
Issue number7061
DOIs
StatePublished - Oct 13 2005
Externally publishedYes

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    Hu, R. G., Sheng, J., Qi, X., Xu, Z., Takahashi, T. T., & Varshavsky, A. (2005). The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature, 437(7061), 981-986. https://doi.org/10.1038/nature04027