Nature 437, 981-986 (13 October 2005) | doi:10.1038/nature04027; Received 26 May 2005; Accepted 15 July 2005

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

Rong-Gui Hu1,4, Jun Sheng1,4, Xin Qi2, Zhenming Xu1,3, Terry T. Takahashi2 & Alexander Varshavsky1

  1. Division of Biology, and
  2. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
  3. †Present address: Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-4120, USA
  4. *These authors contributed equally to this work

Correspondence to: Alexander Varshavsky1 Correspondence and requests for materials should be addressed to A.V. (Email:


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.


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