Krojer Tobias, Pangerl Karen, Kurt Juliane, Sawa Justyna, Stingl Christoph, Mechtler Karl, Huber Robert, Ehrmann Michael, Clausen Tim
Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria.
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7702-7. doi: 10.1073/pnas.0803392105. Epub 2008 May 27.
Aberrant proteins represent an extreme hazard to cells. Therefore, molecular chaperones and proteases have to carry out protein quality control in each cellular compartment. In contrast to the ATP-dependent cytosolic proteases and chaperones, the molecular mechanisms of extracytosolic factors are largely unknown. To address this question, we studied the protease function of DegP, the central housekeeping protein in the bacterial envelope. Our data reveal that DegP processively degrades misfolded proteins into peptides of defined size by employing a molecular ruler comprised of the PDZ1 domain and the proteolytic site. Furthermore, peptide binding to the PDZ domain transforms the resting protease into its active state. This allosteric activation mechanism ensures the regulated and rapid elimination of misfolded proteins upon folding stress. In comparison to the cytosolic proteases, the regulatory features of DegP are established by entirely different mechanisms reflecting the convergent evolution of an extracytosolic housekeeping protease.
异常蛋白质对细胞构成极大危害。因此，分子伴侣和蛋白酶必须在每个细胞区室中进行蛋白质质量控制。与依赖ATP的胞质蛋白酶和伴侣蛋白不同，胞外因子的分子机制在很大程度上尚不清楚。为了解决这个问题，我们研究了DegP的蛋白酶功能，它是细菌包膜中的核心管家蛋白。我们的数据表明，DegP通过使用由PDZ1结构域和蛋白水解位点组成的分子尺，将错误折叠的蛋白质逐步降解为特定大小的肽段。此外，肽与PDZ结构域的结合将静止的蛋白酶转变为其活性状态。这种变构激活机制确保在折叠应激时对错误折叠的蛋白质进行有调节的快速清除。与胞质蛋白酶相比，DegP的调节特性是由完全不同的机制建立的，这反映了胞外管家蛋白酶的趋同进化。
