Phoslactomycin targets cysteine-269 of the protein phosphatase 2A catalytic subunit in cells
Phoslactomycin targets cysteine-269 of the protein phosphatase 2A catalytic subunit in cells
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DOI：
10.1016/j.febslet.2005.03.049
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发表时间：
2005-04-25
期刊：
影响因子：
3.5
通讯作者：
Osada, H
中科院分区：
文献类型：
--
作者：
Teruya, T;Simizu, S;Osada, H
根据化学遗传学方法，直接与蛋白质结合的小分子用于分析蛋白质功能，从而能够阐明哺乳动物细胞中的复杂机制。因此，鉴定在靶细胞中诱导独特表型的化合物的分子靶标是非常重要的。磷霉素A（PLMA）是蛋白质Ser/Thr磷酸酶2A（PP2A）的有效抑制剂，但PLMA对PP2A的抑制机制尚不清楚。在这里，我们证明了PLMA直接结合到细胞中的PP2A催化亚基（PP2Ac），通过使用生物素化PLMA，PLMA结合位点被确定为Cys-269残基的PP2Ac。此外，我们揭示了Cys-269有助于PLMA对PP2Ac活性的有效抑制。这些结果表明，PLMA是一种PP2A选择性抑制剂，因此，预计将是有用的PP2A在细胞中的功能的未来调查。(c)2005年欧洲生物化学学会联合会。Elsevier B.V.出版，保留所有权利。
According to the chemical genetic approach, small molecules that bind directly to proteins are used to analyze protein function, thereby enabling the elucidation of complex mechanisms in mammal cells. Thus, it is very important to identify the molecular targets of compounds that induce a unique phenotype in a target cell. Phoslactomycin A (PLMA) is known to be a potent inhibitor of protein Ser/Thr phosphatase 2A (PP2A); however, the inhibitory mechanism of PP2A by PLMA has not yet been elucidated. Here, we demonstrated that PLMA directly binds to the PP2A catalytic subunit (PP2Ac) in cells by using biotinylated PLMA, and the PLMA-binding site was identified as the Cys-269 residue of PP2Ac. Moreover, we revealed that the Cys-269 contributes to the potent inhibition of PP2Ac activity by PLMA. These results suggest that PLMA is a PP2A-selective inhibitor and is therefore expected to be useful for future investigation of PP2A function in cells. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.