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细胞周期蛋白B3中的磷酸结合口袋对于减数分裂I中XErp1/Emi2的降解至关重要。

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

作者信息

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

机构信息

Department of Biology, University of Konstanz, 78457, Konstanz, Germany.

Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstraße 10, 78457, Konstanz, Germany.

出版信息

EMBO Rep. 2025 Feb;26(3):768-790. doi: 10.1038/s44319-024-00347-8. Epub 2025 Jan 2.

DOI:10.1038/s44319-024-00347-8
PMID:39747666
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11811201/
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.

摘要

为确保胚胎的正确整倍体状态，脊椎动物卵母细胞必须在减数分裂II中期停滞等待受精。这种减数分裂II期停滞由XErp1/Emi2介导，它抑制泛素连接酶APC/C（后期促进复合体/细胞周期体）。与细胞周期蛋白依赖性激酶1（Cdk1）结合的细胞周期蛋白B3（Cyclin B3）通过靶向降解XErp1/Emi2，对于防止脊椎动物卵母细胞在减数分裂I期过早停滞至关重要。然而，减数分裂I期XErp1/Emi2降解的分子机制尚不清楚。在这里，通过将卵母细胞中的TRIM-Away与卵提取物和体外研究相结合，我们证明细胞周期蛋白B3中一个迄今未知的磷酸结合口袋对于减数分裂I期高效降解XErp1/Emi2至关重要。这个口袋使Cdk1/细胞周期蛋白B3能够结合预磷酸化的XErp1/Emi2，促进进一步的磷酸化事件，最终以依赖Polo样激酶1（Plk1）的方式靶向降解XErp1/Emi2。这种降解机制的关键要素在青蛙和小鼠中是保守的。我们的研究确定了一种新的、进化上保守的Cdk/细胞周期蛋白底物特异性决定因素，对于防止卵母细胞在减数分裂I期过早停滞并在受精时产生灾难性后果至关重要。

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