1. Protein degradation of antizyme depends on the N‐terminal degrons.
- Author
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Hsieh, Ju‐Yi, Leong, Pui‐Ying, Yang, Yi‐Fang, Liu, Yi‐Liang, Liu, Guang‐Yaw, and Hung, Hui‐Chih
- Abstract
Antizyme (AZ) is a regulatory protein that plays a crucial role in modulating the activity of ornithine decarboxylase (ODC), which is the initial and rate‐limiting enzyme in the complex pathway of polyamine biosynthesis. AZ facilitates the swift degradation of ODC, thereby modulating the levels of cellular polyamines. This study unveils a new ubiquitin‐independent mechanism for AZ degradation, emphasizing the essential role of N‐terminal degrons. Contrary to traditional ubiquitin‐dependent degradation, our findings reveal that AZ degradation is significantly influenced by its N‐terminal region. By conducting a series of experiments, including in vitro degradation assays, cycloheximide chase experiments, differential scanning calorimetry, and measurement of cellular concentrations of polyamines, we demonstrate that N‐terminal truncation significantly enhances AZ's stability and facilitates the reduction of polyamine levels by accelerating ODC degradation. The removal of the N‐terminal portion of AZ results in a reduced degradation rate and enhanced thermal stability of the protein, leading to a more efficient inhibition of polyamine synthesis. These findings are corroborated by the analysis of AZ isoforms, AZ1, AZ2, and AZ3, which display differential degradation patterns based on the specific N‐terminal segments. This substantiates a degradation mechanism driven by an intrinsically disordered N‐terminal region acting as a degron, independent of lysine ubiquitination. These results underscore the significant regulatory function of the N‐terminal domain in the activity of AZ and the maintenance of polyamine homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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