The Interaction of Nitric Oxide (NO) with the Yeast Transcription Factor Ace1: A Model System for NO-Protein Thiol Interactions with Implications to Metal Metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 6; pp. 2491 - 2496
• Main Authors: Shinyashiki, M, Chiang, K T, Switzer, C H, Gralla, E B, Valentine, J S, Thiele, D J, Fukuto, J M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 14.03.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Ace1 protein; beta-Galactosidase - metabolism; Biological Sciences; Carrier Proteins; Cells; Centrifugation; Chemical reactions; Chemicals; Copper; CUP1 gene; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Fungal Proteins - metabolism; Gene induction; Inductive reasoning; Iron; Metallothionein - metabolism; Metals - metabolism; Models, Chemical; nitric oxide; Nitric Oxide - metabolism; oxygen; Plasmids; Protein metabolism; Proteins; Quaternary Ammonium Compounds - metabolism; Room temperature; Saccharomyces cerevisiae; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins; Sulfhydryl Compounds - metabolism; Thiols; Time Factors; Transcription factors; Transcription Factors - metabolism; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.050586597

Nitric oxide (NO) was found to inhibit the copper-dependent induction of the yeast CUP1 gene. This effect is attributable to an inhibition of the copper-responsive CUP1 transcriptional activator Ace1. A mechanism is proposed whereby the metal binding thiols of Ace1 are chemically modified via NO- and O2-dependent chemistry, thereby diminishing the ability of Ace1 to bind and respond to copper. Moreover, it is proposed that demetallacted Ace1 is proteolytically degraded in the cell, resulting in a prolonged inhibition of copper-dependent CUP1 induction. These findings indicate that NO may serve as a disrupter of yeast copper metabolism. More importantly, considering the similarity of Ace1 to other mammalian metal-binding proteins, this work lends support to the hypothesis that NO may regulate/disrupt metal homeostasis under both normal physiological and pathophysiological circumstances.