Molecular mechanism and functional significance of Wapl interaction with the Cohesin complex

• 成果类型: Article
• 署名作者: Yuan, Xueying; Yan, Lu; Chen, Qinfu; Zhu, Shukai; Zhou, Xinyu; Zeng, Ling - Hui; Liu, Mingjie; He, Xiaojing; Huang, Jun; Lu, Weiguo; Zhang, Long; Yan, Haiyan; Wang, Fangwei
• 署名单位: Zhejiang University; Zhejiang University; Hangzhou City University; Huazhong University of Science & Technology; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10220
• DOI: 10.1073/pnas.2405177121
• 发表日期: 2024-08-13
• 关键词: sister-chromatid cohesion; protein phosphatase 2a; dna exit gate; gene-expression; chromosome arms; shugoshin; removal; sororin; centromeres; distinct

摘要

The ring- shaped Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or its paralog SA1), topologically entraps two duplicated sister DNA molecules to establish sister chromatid cohesion in S- phase. It remains largely elusive how the Cohesin release factor Wapl binds the Cohesin complex, thereby inducing Cohesin disassociation from mitotic chromosomes to allow proper resolution and separation of sister chromatids. Here, we show that Wapl uses two structural modules containing the FGF motif and the YNARHWN motif, respectively, to simultaneously bind distinct pockets in the extensive composite interface between Scc1 and SA2. Strikingly, only when both docking modules are mutated, Wapl completely loses the ability to bind the Scc1- SA2 interface and release Cohesin, leading to erroneous chromosome segregation in mitosis. Surprisingly, Sororin, which contains a conserved FGF motif and functions as a master antagonist of Wapl in S- phase and G2- phase, does not bind the Scc1- SA2 interface. Moreover, Sgo1, the major protector of Cohesin at mitotic centromeres, can only compete with the FGF motif but not the YNARHWN motif of Wapl for binding Scc1- SA2 interface. Our data uncover the molecular mechanism by which Wapl binds Cohesin to ensure precise chromosome segregation.