Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins.
Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins.
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DOI：
10.1038/nchembio.597
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发表时间：
2011-07-03
影响因子：
14.8
通讯作者：
Crews, Craig M.
中科院分区：
文献类型：
--
作者：
Neklesa, Taavi K.;Tae, Hyun Seop;Schneekloth, Ashley R.;Stulberg, Michael J.;Corson, Timothy W.;Sundberg, Thomas B.;Raina, Kanak;Holley, Scott A.;Crews, Craig M.
在具有小分子的生命系统中调节任何感兴趣的蛋白质的能力仍然是一个挑战。我们假设，将疏水部分添加到蛋白质表面将模拟蛋白质的部分变性状态，从而使细胞质量控制机制诱导其蛋白酶体降解。我们设计并合成了与细菌脱卤酶(HaloTag蛋白)结合的双功能小分子，并在其表面呈现一个疏水基团。值得注意的是，用金刚烷基部分疏水标记HaloTag蛋白诱导了细胞培养中胞浆、异戊二烯和跨膜融合蛋白的降解。我们通过降解斑马鱼胚胎中表达的蛋白质和抑制RasG12V驱动的小鼠肿瘤进展，在体内证明了疏水标记的实用性。因此，HaloTag融合蛋白的疏水标记提供了对任何感兴趣的蛋白质的小分子控制，使其成为在疾病模型中验证潜在药物靶点的理想系统。
The ability to regulate any protein of interest in living systems with small molecules remains a challenge. We hypothesized that appending a hydrophobic moiety to the surface of a protein would mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. We designed and synthesized bifunctional small molecules that bind a bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Remarkably, hydrophobic tagging of the HaloTag protein with an adamantyl moiety induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. We demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
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影响因子：
3.7
作者：
Gies E;Wilde I;Winget JM;Brack M;Rotblat B;Novoa CA;Balgi AD;Sorensen PH;Roberge M;Mayor T
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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