A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-01-02 DOI:10.1038/s44319-024-00347-8

Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer

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Abstract

To ensure the correct euploid state of embryos, it is essential that vertebrate oocytes await fertilization arrested at metaphase of meiosis II. This MII arrest is mediated by XErp1/Emi2, which inhibits the ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). Cyclin B3 in complex with Cdk1 (cyclin-dependent kinase 1) is essential to prevent an untimely arrest of vertebrate oocytes in meiosis I by targeting XErp1/Emi2 for degradation. Yet, the molecular mechanism of XErp1/Emi2 degradation in MI is not well understood. Here, by combining TRIM-Away in oocytes with egg extract and in vitro studies, we demonstrate that a hitherto unknown phosphate-binding pocket in cyclin B3 is essential for efficient XErp1/Emi2 degradation in meiosis I. This pocket enables Cdk1/cyclin B3 to bind pre-phosphorylated XErp1/Emi2 facilitating further phosphorylation events, which ultimately target XErp1/Emi2 for degradation in a Plk1- (Polo-like kinase 1) dependent manner. Key elements of this degradative mechanism are conserved in frog and mouse. Our studies identify a novel, evolutionarily conserved determinant of Cdk/cyclin substrate specificity essential to prevent an untimely oocyte arrest at meiosis I with catastrophic consequences upon fertilization.

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细胞周期蛋白B3中的磷酸盐结合袋对于减数分裂I中XErp1/Emi2的降解是必不可少的。

为了保证胚胎的正确整倍体状态，脊椎动物卵母细胞在减数分裂II中期停止等待受精是至关重要的。这种MII阻滞是由XErp1/Emi2介导的，它抑制泛素连接酶APC/C（后期促进复合体/环体）。细胞周期蛋白B3与Cdk1（细胞周期蛋白依赖性激酶1）复合物通过靶向XErp1/Emi2降解来防止脊椎动物卵母细胞在减数分裂I中过早停止是必不可少的。然而，XErp1/Emi2降解在心肌梗死中的分子机制尚不清楚。在这里，通过结合trimm - away卵母细胞与卵提取物和体外研究，我们证明了细胞周期蛋白B3中迄今未知的磷酸盐结合口袋对于减数分裂i中XErp1/Emi2的有效降解是必不可少的。这个口袋使Cdk1/cyclin B3结合预磷酸化的XErp1/Emi2促进进一步的磷酸化事件，最终以Plk1- (Polo-like kinase 1)依赖的方式靶向XErp1/Emi2进行降解。这种降解机制的关键要素在青蛙和小鼠中是保守的。我们的研究发现了一种新的，进化上保守的Cdk/细胞周期蛋白底物特异性决定因素，这对于防止卵母细胞在减数分裂I时过早停滞和受精后的灾难性后果至关重要。

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

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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