Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Mol Cell. 2009 Dec 11;36(5):782-93. doi: 10.1016/j.molcel.2009.10.015.
Protein quality control in the endoplasmic reticulum is of central importance for cellular homeostasis in eukaryotes. Crucial for this process is the HRD-ubiquitin ligase (HMG-CoA reductase degradation), which singles out terminally misfolded proteins and routes them for degradation to cytoplasmic 26S-proteasomes. Certain functions of this enzyme complex are allocated to defined subunits. However, it remains unclear how these components act in a concerted manner. Here, we show that Usa1 functions as a major scaffold protein of the HRD-ligase. For the turnover of soluble substrates, Der1 binding to the C terminus of Usa1 is required. The N terminus of Usa1 associates with Hrd1 and thus bridges Der1 to Hrd1. Strikingly, the Usa1 N terminus also induces oligomerization of the HRD complex, which is an exclusive prerequisite for the degradation of membrane proteins. Our data demonstrate that scaffold proteins are required to adapt ubiquitin ligase activities toward different classes of substrates.
内质网中的蛋白质质量控制对于真核细胞的细胞内稳态至关重要。这一过程的关键是 HRD-泛素连接酶（HMG-CoA 还原酶降解），它可以识别终末错误折叠的蛋白质，并将其定向降解为细胞质 26S-蛋白酶体。该酶复合物的某些功能分配给特定的亚基。然而，这些组件如何协同作用仍不清楚。在这里，我们表明 Usa1 作为 HRD-连接酶的主要支架蛋白发挥作用。对于可溶性底物的周转，Der1 与 Usa1 的 C 末端结合是必需的。Usa1 的 N 末端与 Hrd1 结合，从而将 Der1 与 Hrd1 桥接。引人注目的是，Usa1 N 末端还诱导 HRD 复合物的寡聚化，这是降解膜蛋白的唯一前提。我们的数据表明，支架蛋白对于将泛素连接酶活性适应于不同类别的底物是必需的。
