Molecular Biology Department, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
Mol Cell. 2019 Jul 25;75(2):238-251.e5. doi: 10.1016/j.molcel.2019.05.035. Epub 2019 Jul 16.
BRCT domains support myriad protein-protein interactions involved in genome maintenance. Although di-BRCT recognition of phospho-proteins is well known to support the genotoxic response, whether multi-BRCT domains can acquire distinct structures and functions is unclear. Here we present the tetra-BRCT structures from the conserved yeast protein Rtt107 in free and ligand-bound forms. The four BRCT repeats fold into a tetrahedral structure that recognizes unmodified ligands using a bi-partite mechanism, suggesting repeat origami enabling function acquisition. Functional studies show that Rtt107 binding of partner proteins of diverse activities promotes genome replication and stability in both distinct and concerted manners. A unified theme is that tetra- and di-BRCT domains of Rtt107 collaborate to recruit partner proteins to chromatin. Our work thus illustrates how a master regulator uses two types of BRCT domains to recognize distinct genome factors and direct them to chromatin for constitutive genome protection.
BRCT 结构域支持参与基因组维护的众多蛋白质-蛋白质相互作用。尽管双 BRCT 识别磷酸化蛋白已被广泛认为支持遗传毒性反应，但多 BRCT 结构域是否能够获得独特的结构和功能尚不清楚。在这里，我们展示了来自保守酵母蛋白 Rtt107 的游离和配体结合形式的四 BRCT 结构。四个 BRCT 重复折叠成一个四面体结构，使用双部分机制识别未修饰的配体，这表明重复折纸能够实现功能获得。功能研究表明，Rtt107 与不同活性的伴侣蛋白的结合促进了基因组在不同和协同方式中的复制和稳定性。一个统一的主题是，Rtt107 的四 BRCT 和双 BRCT 结构域协同招募伴侣蛋白到染色质。因此，我们的工作说明了主调节因子如何使用两种类型的 BRCT 结构域来识别不同的基因组因子，并将它们引导到染色质以进行组成型基因组保护。
