Exposed hydrophobicity is a key determinant of nuclear quality control degradation.
Exposed hydrophobicity is a key determinant of nuclear quality control degradation.
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DOI：
10.1091/mbc.e11-03-0256
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发表时间：
2011-07-01
影响因子：
3.3
通讯作者：
Gardner RG
中科院分区：
文献类型：
--
作者：
Fredrickson EK;Rosenbaum JC;Locke MN;Milac TI;Gardner RG
酵母核蛋白质质量控制泛素连接酶San1识别其错误折叠底物中暴露的疏水性。San1识别通过暴露少至5个连续的疏水残基来触发，这限定了San1靶向所需的最小疏水性窗口。蛋白质质量控制（PQC）降解通过防止错误折叠蛋白质的毒性积累来保护细胞。在真核生物中，PQC降解主要通过泛素连接酶实现，所述泛素连接酶将泛素连接至错误折叠的蛋白质以进行蛋白酶体降解。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蛋白质中常见的结构异常属性来区分错误折叠蛋白质与其正常对应物。然而，大多数PQC泛素连接酶识别的结构异常特征的性质是未知的。在这里，我们证明了酵母核PQC泛素连接酶San1识别暴露在其底物的疏水性。San1识别通过暴露少至5个连续的疏水残基来触发，这限定了San1靶向所需的最小疏水性窗口。我们还发现，San1识别的暴露的疏水性可以引起聚集和细胞毒性，强调了San1介导的PQC降解错误折叠的核蛋白的基本保护作用。
The yeast nuclear protein quality control ubiquitin ligase San1 recognizes exposed hydrophobicity in its misfolded 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. 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.