Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, 1945 Colorado Avenue, Boulder, CO 80309, USA.
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, 1945 Colorado Avenue, Boulder, CO 80309, USA.
Cell Rep. 2022 Jun 7;39(10):110918. doi: 10.1016/j.celrep.2022.110918.
The proteasome holoenzyme regulates the cellular proteome via degrading most proteins. In its 19-subunit regulatory particle (RP), a heterohexameric ATPase enables protein degradation by injecting protein substrates into the core peptidase. RP assembly utilizes "checkpoints," where multiple dedicated chaperones bind to specific ATPase subunits and control the addition of other subunits. Here, we find that the RP assembly checkpoint relies on two common features of the chaperones. Individual chaperones can distinguish an RP, in which their cognate ATPase persists in the ATP-bound state. Chaperones then together modulate ATPase activity to facilitate RP subunit rearrangements for switching to an active, substrate-processing state in the resulting proteasome holoenzyme. Thus, chaperones may sense ATP binding and hydrolysis as a readout for the quality of the RP complex to generate a functional proteasome holoenzyme. Our findings provide a basis to potentially exploit the assembly checkpoints in situations with known deregulation of proteasomal ATPase chaperones.
蛋白酶体全酶通过降解大多数蛋白质来调节细胞蛋白质组。在其 19 个亚基的调节颗粒 (RP) 中，一个异六聚体 ATP 酶通过将蛋白质底物注入核心肽酶来促进蛋白质降解。RP 组装利用“检查点”，其中多个专用伴侣蛋白结合到特定的 ATP 酶亚基上，并控制其他亚基的添加。在这里，我们发现 RP 组装检查点依赖于伴侣蛋白的两个共同特征。单个伴侣蛋白可以区分其同源 ATP 酶持续处于 ATP 结合状态的 RP。然后，伴侣蛋白共同调节 ATP 酶活性，以促进 RP 亚基重排，从而在产生的蛋白酶体全酶中切换到活跃的、底物处理状态。因此，伴侣蛋白可以将 ATP 结合和水解作为 RP 复合物质量的读出信号，以产生功能性蛋白酶体全酶。我们的发现为在已知蛋白酶体 ATP 酶伴侣蛋白失调的情况下在原位利用组装检查点提供了基础。
