Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Mol Biol Cell. 2011 Jul 1;22(13):2384-95. doi: 10.1091/mbc.E11-03-0256. Epub 2011 May 5.
Protein quality control (PQC) degradation protects the cell by preventing the toxic accumulation of misfolded proteins. In eukaryotes, PQC degradation is primarily achieved by ubiquitin ligases that attach ubiquitin to misfolded proteins for proteasome degradation. To function effectively, PQC ubiquitin ligases must distinguish misfolded proteins from their normal counterparts by recognizing an attribute of structural abnormality commonly shared among misfolded proteins. However, the nature of the structurally abnormal feature recognized by most PQC ubiquitin ligases is unknown. Here we demonstrate that the yeast nuclear PQC ubiquitin ligase San1 recognizes exposed hydrophobicity in its substrates. San1 recognition is triggered by exposure of as few as five contiguous hydrophobic residues, which defines the minimum window of hydrophobicity required for San1 targeting. We also find that the exposed hydrophobicity recognized by San1 can cause aggregation and cellular toxicity, underscoring the fundamental protective role for San1-mediated PQC degradation of misfolded nuclear proteins.
蛋白质质量控制 (PQC) 降解通过防止错误折叠的蛋白质积累来保护细胞。在真核生物中，PQC 降解主要通过泛素连接酶来实现，该酶将泛素连接到错误折叠的蛋白质上，以便进行蛋白酶体降解。为了有效地发挥作用，PQC 泛素连接酶必须通过识别错误折叠的蛋白质与正常蛋白质之间共有的结构异常属性来区分错误折叠的蛋白质。然而，大多数 PQC 泛素连接酶识别的结构异常特征的性质尚不清楚。在这里，我们证明酵母核 PQC 泛素连接酶 San1 识别其底物中的暴露疏水性。San1 的识别是由多达五个连续的疏水性残基暴露引发的，这定义了 San1 靶向所需的最小疏水性窗口。我们还发现，San1 识别的暴露疏水性会导致聚集和细胞毒性，突出了 San1 介导的错误折叠核蛋白的 PQC 降解的基本保护作用。
