Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.
Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8. Epub 2018 Dec 31.
Aberrant cleavage of Notch by γ-secretase leads to several types of cancer, but how γ-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human γ-secretase in complex with a Notch fragment at a resolution of 2.7 Å. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal β-strand of the Notch fragment forms a β-sheet with two substrate-induced β-strands of PS1 on the intracellular side. Formation of the hybrid β-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by γ-secretase.
γ-分泌酶对 Notch 的异常切割会导致多种类型的癌症，但γ-分泌酶如何识别其底物仍不清楚。在这里，我们报道了分辨率为 2.7Å 的人γ-分泌酶与 Notch 片段复合物的低温电子显微镜结构。Notch 的跨膜螺旋被 PS1 的三个跨膜结构域包围，Notch 片段的羧基末端β-链在细胞内与 PS1 的两个底物诱导的β-链形成β-片层。杂合β-片层的形成对于发生在 Notch 跨膜螺旋羧基末端的底物切割至关重要。PS1 在结合底物后会发生明显的构象重排。这些特征揭示了 Notch 识别的结构基础，并对 γ-分泌酶募集淀粉样前体蛋白具有启示意义。
