Ever HRD a ubiquitin-gated channel?
Ever HRD a ubiquitin-gated channel?
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HRD 曾经是泛素门控通道吗？
DOI：
10.1038/cr.2016.92
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发表时间：
2016
期刊：
影响因子：
44.1
通讯作者：
Ye,Yihong
中科院分区：
文献类型：
--
作者：
Zhang,Ting;Ye,Yihong
在内质网（ER）中，蛋白质合成的保真度由内质网相关蛋白降解（ERAD）来保证。该途径将异常多肽从内质网逆转录到细胞质中，由蛋白酶体[1]降解。在酿酒酵母中，几种膜嵌入的泛素连接酶负责逆转录易位产物的泛素化：Hrd1泛素化底物在管腔和膜中携带错误折叠结构域；Doa10处理携带错误折叠细胞质结构域的底物[2,3]。ERAD的一个关键但尚未明确的步骤是多肽跨膜易位，假定是通过泛素连接酶（如Hrd1[4]）形成的导管发生的。在最近一期的《细胞》杂志上，Baldridge和Rapoport证明Hrd1确实是一种蛋白质逆转录转运通道[5]。为了重建一个模拟逆转录过程的反应，Baldridge生成了携带Pdr5或Spt23跨膜片段的CPY*变体（称为CPY*-TMs）。与CPY*[6]类似，CPY*-TMs在细胞内也被Hrd1降解，在体外，只有CPY*-TMs能被Hrd1有效地泛素化，而折叠后的CPY*-TMs不能被Hrd1有效地泛素化。重要的是，CPY*-TMs可以有效地纳入
In the endoplasmic reticulum (ER), the fidelity of protein synthesis is safeguarded by ER-associated protein degradation (ERAD). This pathway retrotranslocates aberrant polypeptides from the ER to the cytosol for degradation by the proteasome [1]. In S. cerevisiae, several membrane-embedded ubiquitin ligases are responsible for ubiquitination of retrotranslocated products: Hrd1 ubiquitinates substrates bearing misfolded domains in the lumen and membranes; Doa10 deals with substrates carrying a misfolded cytosolic domain [2, 3]. A key, yet poorly-defined step in ERAD is the translocation of polypeptide across the membrane, postulated to occur through conduits formed by ubiquitin ligases such as Hrd1 [4]. In a recent issue of Cell, Baldridge and Rapoport demonstrate that Hrd1 is indeed a protein retrotranslocation channel [5].To reconstitute a reaction that simulates closely the retrotranslocation process, Baldridge generated CPY* variants carrying a transmembrane segment from either Pdr5 or Spt23 (referred to as CPY*-TMs). Similar to CPY*[6], CPY*-TMs were degraded by Hrd1 in cells, and in vitro, only CPY*-TMs, but not the folded counterparts could be efficiently ubiquitinated by Hrd1 in detergent. Importantly, CPY*-TMs could be efficiently incorporated into