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PNAS:揭示机体常见酶类PP1的特殊行为机制

来源:生物谷 2014-03-04 23:28

2014年3月5日 讯 /生物谷BIOON/ --近日,刊登在国际杂志PNAS上的一篇研究报告中,来自美国布朗大学的研究人员揭示了一种名为PP1酶类的特殊行为,该酶类参与了机体多种疾病的发生,比如癌症;PP1在细胞中可以扮演分子通道的角色,其在机体随处可见,由于其普遍性,因此其并不能作为药物的靶点来进行开发。

研究者Page教授说道,由于PP1在机体中随处可见,因此没有人会以其作为药物开发的靶点,但是通过作用PP1的活性位点或许可以开发用于治疗药物成瘾、阿尔兹海默氏症等疾病。

文章中研究者想知道是什么促使PP1在特殊情况下发生特殊的行为,PP1可以结合超过200中不同的蛋白质,这些蛋白质的信息科学家们都知道,但是并不知道其结合的分子机制,PP1同这些蛋白质之间相互结合影响的分子机制尚不清楚;如今研究者利用核磁共振波谱法、X射线晶体衍射法以及生化技术揭示了PP1如何结合到靶向蛋白PNUTS上,该蛋白可以形成结合区域。

早期研究中研究人员发现了两种结合蛋白:NIPP1和脲酶,正因为发现了这两种结合蛋白才使得研究人员发现PP1可以和43种特殊的调节蛋白进行结合从而赋予其特殊的行为;当然NIPP1和脲酶的识别也帮助研究者鉴别出了两种新型的结合区,通过对比和PP1结合的蛋白质的特殊区域,研究者预测和PP1结合的蛋白质中的20%都是以同一种方式与PP1进行作用的。

最后研究者Page表示,目前我们尚不清楚PP1同其它80%的结合蛋白之间的作用方式及作用机制,但是相信通过我们后期的努力会解析出更多结合蛋白同PP1的作用机制。(生物谷Bioon.com)

doi:10.1073/pnas.1317395111
Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code

Meng S. Choya, Martina Hiekea, Ganesan Senthil Kumara, Greyson R. Lewisb, Kristofer R. Gonzalez-DeWhitta, Rene P. Kesslera, Benjamin J. Steina, Manuel Hessenbergerb, Angus C. Nairnc, Wolfgang Petia,d, and Rebecca Pageb,1

The serine/threonine protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. However, how these proteins direct PP1 specificity and the ability to predict how these PP1 interacting proteins bind PP1 from sequence alone is still missing. PP1 nuclear targeting subunit (PNUTS) is a PP1 targeting protein that, with PP1, plays a central role in the nucleus, where it regulates chromatin decondensation, RNA processing, and the phosphorylation state of fundamental cell cycle proteins, including the retinoblastoma protein (Rb), p53, and MDM2. The molecular function of PNUTS in these processes is completely unknown. Here, we show that PNUTS, which is intrinsically disordered in its free form, interacts strongly with PP1 in a highly extended manner. Unexpectedly, PNUTS blocks one of PP1’s substrate binding grooves while leaving the active site accessible. This interaction site, which we have named the arginine site, allowed us to define unique PP1 binding motifs, which advances our ability to predict how more than a quarter of the known PP1 regulators bind PP1. Additionally, the structure shows how PNUTS inhibits the PP1-mediated dephosphorylation of critical substrates, especially Rb, by blocking their binding sites on PP1, insights that are providing strategies for selectively enhancing Rb activity.

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