Department of Gynecologic Oncology of Women's Hospital, School of Medicine and MOE Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
Proc Natl Acad Sci U S A. 2024 Aug 13;121(33):e2405177121. doi: 10.1073/pnas.2405177121. Epub 2024 Aug 7.
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.
由核心亚基 Smc1、Smc3、Scc1 和 SA2（或其同源物 SA1）组成的环形黏合蛋白复合物，拓扑学上束缚两个复制的姐妹 DNA 分子，以在 S 期建立姐妹染色单体黏合。Wapl 如何结合黏合蛋白复合物从而诱导黏合蛋白从有丝分裂染色体上解离，以允许姐妹染色单体正确分离和分离，这在很大程度上仍不清楚。在这里，我们表明 Wapl 使用包含 FGF 基序和 YNARHWN 基序的两个结构模块，分别结合 Scc1 和 SA2 之间广泛的复合界面上的不同口袋。引人注目的是，只有当两个对接模块都发生突变时，Wapl 才完全失去与 Scc1-SA2 界面结合的能力并释放黏合蛋白，导致有丝分裂中染色体分离错误。令人惊讶的是， Sororin 含有保守的 FGF 基序，在 S 期和 G2 期作为 Wapl 的主要拮抗剂，不与 Scc1-SA2 界面结合。此外，Sgo1 是有丝分裂着丝粒处黏合蛋白的主要保护蛋白，只能与 FGF 基序竞争结合 Scc1-SA2 界面，而不能与 Wapl 的 YNARHWN 基序竞争。我们的数据揭示了 Wapl 结合黏合蛋白以确保精确染色体分离的分子机制。
