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Research ArticleArticle

Ubiquitination and Degradation of Neuronal Nitric-Oxide Synthase in Vitro: Dimer Stabilization Protects the Enzyme from Proteolysis

Anwar Y. Dunbar, Yasuhiko Kamada, Gary J. Jenkins, Ezra R. Lowe, Scott S. Billecke and Yoichi Osawa
Molecular Pharmacology October 2004, 66 (4) 964-969; DOI: https://doi.org/10.1124/mol.104.000125
Anwar Y. Dunbar
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Yasuhiko Kamada
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Gary J. Jenkins
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Ezra R. Lowe
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Scott S. Billecke
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Yoichi Osawa
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Abstract

It is established that neuronal NO synthase (nNOS) is ubiquitinated and proteasomally degraded. The metabolism-based inactivation of nNOS and the inhibition of heat shock protein 90 (hsp90)-based chaperones, which are known to regulate nNOS, both lead to enhanced proteasomal degradation of nNOS. The mechanism of this selective proteolytic degradation, or in essence how the nNOS becomes labilized and recognized for ubiquitination and subsequent degradation, has not been determined. In the current study, we used a crude preparation of reticulocyte proteins, which contains ubiquitin-conjugating enzymes and the proteasome, to determine how nNOS is labilized. We found that the inactive monomeric heme-deficient nNOS (apo-nNOS) is rapidly degraded in vitro, consistent with the finding that both metabolism-based inactivation and inhibition of hsp90-based chaperones cause the formation of apo-nNOS and enhance its degradation in vivo. In the current study, we discovered that destabilization of the dimeric nNOS, as determined by measuring the SDS-resistant dimer, is sufficient to trigger ubiquitin-proteasomal degradation. Treatment of nNOS with NG-nitro-l-arginine or 7-nitroindazole led to stabilization of the dimeric nNOS and decreased proteasomal degradation of the enzyme, consistent with that observed in cells. Thus, it seems that the dimeric structure is a major determinant of nNOS stability and proteolysis.

  • Received March 5, 2004.
  • Accepted July 2, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (4)
Molecular Pharmacology
Vol. 66, Issue 4
1 Oct 2004
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Research ArticleArticle

Ubiquitination and Degradation of Neuronal Nitric-Oxide Synthase in Vitro: Dimer Stabilization Protects the Enzyme from Proteolysis

Anwar Y. Dunbar, Yasuhiko Kamada, Gary J. Jenkins, Ezra R. Lowe, Scott S. Billecke and Yoichi Osawa
Molecular Pharmacology October 1, 2004, 66 (4) 964-969; DOI: https://doi.org/10.1124/mol.104.000125

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Research ArticleArticle

Ubiquitination and Degradation of Neuronal Nitric-Oxide Synthase in Vitro: Dimer Stabilization Protects the Enzyme from Proteolysis

Anwar Y. Dunbar, Yasuhiko Kamada, Gary J. Jenkins, Ezra R. Lowe, Scott S. Billecke and Yoichi Osawa
Molecular Pharmacology October 1, 2004, 66 (4) 964-969; DOI: https://doi.org/10.1124/mol.104.000125
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