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Cryo-EM structure of the human CST–Polα/primase complex in a recruitment state
Nature Structural & Molecular Biology ( IF 16.8 ) Pub Date : 2022-05-16 , DOI: 10.1038/s41594-022-00766-y
Sarah W Cai 1, 2 , John C Zinder 1 , Vladimir Svetlov 3, 4 , Martin W Bush 2 , Evgeny Nudler 3, 4 , Thomas Walz 2 , Titia de Lange 1
Affiliation  

The CST–Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST–Polα/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking. Our structure reveals an evolutionarily conserved interaction between the C-terminal domain of the catalytic POLA1 subunit and an N-terminal expansion in metazoan CTC1. Cross-linking mass spectrometry and negative-stain EM analysis provide insight into CST binding by the flexible POLA1 N-terminus. Finally, Coats plus syndrome disease mutations previously characterized to disrupt formation of the CST–Polα/primase complex map to protein–protein interfaces observed in the recruitment state. Together, our results shed light on the architecture and stoichiometry of the metazoan fill-in machinery.



中文翻译:

处于募集状态的人类 CST–Polα/primase 复合物的冷冻电镜结构

CST–Polα/引物酶复合物对于端粒维护和功能以抵消双链断裂处的切除是必不可少的。我们报告了人 CST-Polα/引物酶的 4.6-Å 分辨率冷冻电镜结构,该结构在催化之前捕获,处于通过化学交联稳定的募集状态。我们的结构揭示了催化 POLA1 亚基的 C 端结构域与后生动物 CTC1 的 N 端扩展之间的进化保守相互作用。交联质谱法和负染色 EM 分析提供了对柔性 POLA1 N 末端 CST 结合的深入了解。最后,Coats plus 综合征疾病突变先前的特征是破坏 CST-Polα/引物酶复合物的形成,映射到在募集状态下观察到的蛋白质-蛋白质界面。一起,

更新日期:2022-05-17
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