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

Nature. 2005 Oct 13;437(7061):981-6. doi: 10.1038/nature04027.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoacyltransferases / deficiency
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism*
  • Animals
  • Arginine / metabolism*
  • Cardiovascular Abnormalities / genetics
  • Cardiovascular Abnormalities / metabolism
  • Cysteine / metabolism*
  • Embryo, Mammalian / metabolism
  • Eye Proteins / metabolism
  • Mice
  • Nitric Oxide / analysis
  • Nitric Oxide / metabolism*
  • Oxidation-Reduction
  • Oxygen / metabolism
  • RGS Proteins / metabolism


  • Eye Proteins
  • RGS Proteins
  • RGS16 protein
  • Rgs5 protein, mouse
  • RGS4 protein
  • Nitric Oxide
  • Arginine
  • Aminoacyltransferases
  • arginyltransferase
  • Cysteine
  • Oxygen