Yu Zanlin, Yu Yadong, Wang Feng, Myasnikov Alexander G, Coffino Philip, Cheng Yifan
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, USA.
TrueBinding Inc., 1140A O'Brien, Menlo Park, CA, 94025, USA.
Nat Commun. 2020 Sep 11;11(1):4580. doi: 10.1038/s41467-020-18415-7.
Proteasomal machinery performs essential regulated protein degradation in eukaryotes. Classic proteasomes are symmetric, with a regulatory ATPase docked at each end of the cylindrical 20S. Asymmetric complexes are also present in cells, either with a single ATPase or with an ATPase and non-ATPase at two opposite ends. The mechanism that populates these different proteasomal complexes is unknown. Using archaea homologs, we construct asymmetric forms of proteasomes. We demonstrate that the gate conformation of the two opposite ends of 20S are coupled: binding one ATPase opens a gate locally, and also opens the opposite gate allosterically. Such allosteric coupling leads to cooperative binding of proteasomal ATPases to 20S and promotes formation of proteasomes symmetrically configured with two identical ATPases. It may also promote formation of asymmetric complexes with an ATPase and a non-ATPase at opposite ends. We propose that in eukaryotes a similar mechanism regulates the composition of the proteasomal population.
蛋白酶体机制在真核生物中执行重要的受调控的蛋白质降解。经典蛋白酶体是对称的，一个调节性ATP酶停靠在圆柱形20S的两端。细胞中也存在不对称复合物，要么在两端各有一个单一的ATP酶，要么在两端分别有一个ATP酶和一个非ATP酶。形成这些不同蛋白酶体复合物的机制尚不清楚。我们利用古细菌同源物构建了不对称形式的蛋白酶体。我们证明20S两端的门控构象是相互偶联的：结合一个ATP酶会局部打开一个门，同时也会变构打开相对的门。这种变构偶联导致蛋白酶体ATP酶与20S协同结合，并促进由两个相同ATP酶对称配置的蛋白酶体的形成。它也可能促进在两端分别有一个ATP酶和一个非ATP酶的不对称复合物的形成。我们提出，在真核生物中，类似的机制调节蛋白酶体群体的组成。
