Conditional Binding of Arsenic Trioxide (ATO) to Cysteine-Rich Zinc Finger Motifs within RBCC Domain of PML Protein.

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-12 DOI:10.1021/acs.chemrestox.5c00087

Pei Han Yu, Yu-Ki Tanaka, Yang Gao, Gaowa Wureng, Chen Ying Zhu, Yuan Yuan Kang, Chang Yang, Xin Wang, Yasumitsu Ogra, Hua Naranmandura

引用次数: 0

Abstract

The arsenic trioxide (ATO)-based cure of acute promyelocytic leukemia is attributed to PML/RARα oncoprotein degradation through binding of its RBCC domain (i.e., consist of RING, B-box1, B-box2, and Coiled-coil) with arsenic. Despite ATO being proven to interact with the Cysteine213 triad in the B-box2 trimer of PML-Nuclear Bodies, whether its direct binding to cysteine-rich zinc finger motifs in PML protein, remains unclear. Consequently, we purified the RING, B-box1, and B-box2 domains to assess their potential for arsenic-binding. The results showed that ATO cannot displace zinc ions under physiological conditions but binds with zinc finger domains under zinc-depletion in low-pH conditions, revealing a conditional binding mechanism.

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三氧化二砷（ATO）与PML蛋白RBCC结构域富含半胱氨酸的锌指基元的条件结合。

基于三氧化二砷（ATO）的急性早髓细胞白血病的治疗归因于PML/RARα癌蛋白通过其RBCC结构域（即由RING， B-box1， B-box2和coil -coil组成）与砷结合而降解。尽管ATO已被证明与PML核体B-box2三聚体中的半胱氨酸213三联体相互作用，但其是否与PML蛋白中富含半胱氨酸的锌指基序直接结合尚不清楚。因此，我们纯化了RING、B-box1和B-box2结构域，以评估它们与砷结合的潜力。结果表明，ATO在生理条件下不能置换锌离子，但在低ph条件下，ATO与锌指结构域结合，揭示了一种条件结合机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Research in Toxicology 医学-毒理学

CiteScore

7.90

自引率

7.30%

发文量

215

审稿时长

3.5 months

期刊介绍： Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.