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 and Alexander Varshavsky ()
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Rong-Gui Hu: California Institute of Technology
Jun Sheng: California Institute of Technology
Xin Qi: California Institute of Technology
Zhenming Xu: California Institute of Technology
Terry T. Takahashi: California Institute of Technology
Alexander Varshavsky: California Institute of Technology

Nature, 2005, vol. 437, issue 7061, 981-986

Abstract: 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.

Date: 2005
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DOI: 10.1038/nature04027

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