Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1‐Mediated Proteolysis of CENP‐A

Autor: Yan Peng, Yumeng Zhang, Ruan Fang, Hao Jiang, Gongcai Lan, Zhou Xu, Yajie Liu, Zhaoyang Nie, Lu Ren, Fengcan Wang, Shou‐De Zhang, Yuyong Ma, Peng Yang, Hong‐Hua Ge, Wei‐Dong Zhang, Cheng Luo, Ang Li, Weiwei He
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Advanced Science, Vol 11, Iss 29, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 2198-3844
20230559
DOI: 10.1002/advs.202305593
Popis: Abstract Centromere protein A (CENP‐A), a centromere‐specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure‐activity relationship (SAR) study of the cell‐cycle‐arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)‐6‐Br‐JP18 and (+)‐6‐Cl‐JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X‐ray crystallography analysis reveals that both molecules bind to the colchicine‐binding site of β‐tubulin. Treatment of human cells with microtubule‐targeting agents (MTAs), including these two compounds, results in CENP‐A accumulation by destabilizing Cdh1, a co‐activator of the anaphase‐promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP‐A accumulation using small‐molecule tools and highlights the role of Cdh1 in CENP‐A proteolysis.
Databáze: Directory of Open Access Journals
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