Discovery of a Small-Molecule-Dependent Photolytic Peptide
Discovery of a Small-Molecule-Dependent Photolytic Peptide
复制标题
小分子依赖性光解肽的发现
DOI：
10.1021/jacs.9b09178
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发表时间：
2020
影响因子：
15
通讯作者：
Motonari Uesugi
中科院分区：
文献类型：
--
作者：
Yasushi Takemoto;Di Mao;Louvy Lynn Punzalan;Sebastian Goetze;Shin-ichi Sato;Motonari Uesugi
我们偶然发现YM-53601，一种已知的角鲨烯合酶（SQS）的小分子抑制剂，在紫外线照射后选择性地消耗哺乳动物细胞中的SQS。进一步的分析表明SQS的光耗尽需要其位于COOH末端的短肽段。值得注意的是，当27个氨基酸的肽在NH 2或COOH末端融合到绿色荧光蛋白或不相关的蛋白质时，当用YM-53601和UV暴露处理细胞时，这样的融合蛋白被选择性地耗尽。产物分析和电子自旋共振实验表明，紫外线照射促进了YM-53601中芳基醚基团的均裂C-O键断裂。很可能由UV活化的YM-53601产生的自由基物质从SQS肽中提取氢原子，导致整个蛋白质的光解。在本研究中发现的SQS肽和YM-53601的配对为设计新的小分子控制的光遗传学工具铺平了道路。
We accidentally found that YM-53601, a known small-molecule inhibitor of squalene synthase (SQS), selectively depletes SQS from mammalian cells upon UV irradiation. Further analyses indicated that the photodepletion of SQS requires its short peptide segment located at the COOH terminus. Remarkably, when the 27 amino acid peptide was fused to green fluorescent protein or unrelated proteins at either the NH2or COOH terminus, such fusion proteins were selectively depleted when the cells were treated with both YM-53601 and UV exposure. Product analysis and electron spin resonance experiments suggested that the UV irradiation promotes homolytic C–O bond cleavage of the aryl ether group in YM-53601. It is likely that the radical species generated from UV-activated YM-53601 abstract hydrogen atoms from the SQS peptide, leading to the photolysis of the entire protein. The pair of the SQS peptide and YM-53601 discovered in the present study paves the way for the design of a new small-molecule-controlled optogenetic tool.