Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Structure. 2013 Sep 3;21(9):1624-35. doi: 10.1016/j.str.2013.06.023. Epub 2013 Aug 1.
The 26S proteasome is the major ATP-dependent protease in eukaryotes and thus involved in regulating a diverse array of vital cellular processes. Three subcomplexes form this massive degradation machine: the lid, the base, and the core. While assembly of base and core has been well-studied, the detailed molecular mechanisms involved in formation of the nine-subunit lid remain largely unknown. Here, we reveal that helices found at the C terminus of each lid subunit form a helical bundle that directs the ordered self-assembly of the lid subcomplex. Furthermore, we use an integrative modeling approach to gain critical insights into the bundle topology and provide an important structural framework for our biochemical data. We show that the helical bundle serves as a hub through which the last-added subunit Rpn12 monitors proper lid assembly before incorporation into the proteasome. Finally, we predict that the assembly of the COP9 signalosome depends on a similar helical bundle.
26S 蛋白酶体是真核生物中主要的依赖于 ATP 的蛋白酶，因此参与调节多种重要的细胞过程。三个亚基组成了这个庞大的降解机器：盖子、底座和核心。虽然底座和核心的组装已经得到了很好的研究，但九个亚基盖子的详细分子机制在很大程度上仍然未知。在这里，我们揭示了每个盖子亚基 C 末端发现的螺旋形成一个螺旋束，指导盖子亚基复合物的有序自组装。此外，我们使用一种综合建模方法深入了解了该束的拓扑结构，并为我们的生化数据提供了一个重要的结构框架。我们表明，螺旋束作为一个枢纽，最后添加的亚基 Rpn12 在整合到蛋白酶体之前，通过它来监测盖子组装是否正确。最后，我们预测 COP9 信号osome 的组装依赖于类似的螺旋束。
