Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 1, Pages 76-81Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710568105
Keywords
arginylation; ATE1; ubiquitin; UBR1
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Funding
- NIDDK NIH HHS [R56 DK039520, DK39520, R37 DK039520, R01 DK039520] Funding Source: Medline
- NIGMS NIH HHS [GM31530, R01 GM031530] Funding Source: Medline
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The conjugation of arginine, by arginyl-transferase, to IN-terminal aspartate, glutamate or oxidized cysteine is a part of the Wend rule pathway of protein degradation. We report that arginyl-transferase of either the mouse or the yeast Saccharomyces cerevisiae is inhibited by hemin (Fe3+-heme). Furthermore, we show that hemin inhibits arginyl-transferase through a redox mechanism that involves the formation of disulfide between the enzyme's Cys-71 and Cys-72 residues. Remarkably, hemin also induces the proteasome-dependent degradation of arginyl-transferase in vivo, thus acting as both a stoichiometric and catalytic down-regulator of the Wend rule pathway. In addition, hemin was found to interact with the yeast and mouse E3 ubiquitin ligases of the Wend rule pathway. One of substrate-binding sites of the yeast Wend rule's ubiquitin ligase UBR1 targets CUP9, a transcriptional repressor. This site of UBR1 is autoinhibited but can be allosterically activated by peptides that bear destabilizing N-terminal residues and interact with two other substrate-binding sites of UBR1. We show that hemin does not directly occlude the substrate-binding sites of UBR1 but blocks the activation of its CUP9-binding site by dipeptides. The Wend rule pathway, a known sensor of short peptides, nitric oxide, and oxygen, is now a sensor of heme as well. One function of the Wend rule pathway may be to coordinate the activities of small effectors, both reacting to and controlling the redox dynamics of heme, oxygen, nitric oxide, thiols, and other compounds, in part through conditional degradation of specific transcription factors and G protein regulators.
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