Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.
Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.
复制标题
DOI：
10.1158/2159-8290.cd-23-0453
复制
发表时间：
2023-12-12
期刊：
影响因子：
28.2
通讯作者：
中科院分区：
文献类型：
--
作者：
揭示了PML B-box-2晶体结构，其驱动B2三聚体组装和半胱氨酸三聚体的定位以产生理想的砷结合口袋，其中B2三聚体和半胱氨酸三聚体对于PML介导的功能（包括氧化应激反应）是强制性的。PML核体（NB）在PML-RARA驱动的急性早幼粒细胞白血病（APL）中被破坏。三氧化二砷（ATO）治愈了70%的APL患者，促进了PML-RARA降解和NB再形成。在非APL细胞中，与PML结合的砷也会增强NB的形成。然而，涉及的实际分子机制仍然难以捉摸。在此，我们确定PML NBs显示了一些液-液相分离的特征，ATO诱导了凝胶状转变。PML B-box-2结构揭示了驱动B2三聚化和定位半胱氨酸三聚体以形成理想的砷结合口袋的α螺旋。改变后一种情况会阻碍ATO驱动的NB组装、PML磺酰化和PML-RARA降解，从机制上解释了临床ATO耐药。该B2三聚体和C213三聚体形成了氧化敏感变阻器，其在基础状态和应激反应期间控制PML NB组装动力学和下游信号传导。这些发现确定了砷靶向PML的结构基础，这可能为新型癌症药物铺平道路。砷对APL的疗效依赖于PML靶向。我们报告了PML B-box-2结构，该结构驱动三聚体组装，定位半胱氨酸三联体形成砷结合口袋，在耐药患者中被破坏。鉴定这种控制PML动力学和功能的ROS敏感三联体可以产生新的药物。 见Salomoni的相关评注，第2505页。 这篇文章是精选文章从这个问题，第2489页
A PML B-box-2 crystal structure was revealed that drives B2 trimer assembly and the positioning of a cysteine trio to create an ideal arsenic-binding pocket, with both B2 trimerization and the cysteine trio being mandatory for PML-mediated functions, including an oxidative stress response. PML nuclear bodies (NB) are disrupted in PML-RARA–driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid–liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs. Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs. See related commentary by Salomoni, p. 2505. This article is featured in Selected Articles from This Issue, p. 2489