Heparin Activates PKR by Inducing Dimerization
Heparin Activates PKR by Inducing Dimerization
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DOI：
10.1016/j.jmb.2011.09.025
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发表时间：
2011-11-11
影响因子：
5.6
通讯作者：
Cole, James L.
中科院分区：
文献类型：
--
作者：
Anderson, Eric;Pierre-Louis, Willythssa S.;Cole, James L.
蛋白激酶R（PKR）是一种干扰素诱导的激酶，在先天免疫途径中起着关键作用。PKR在与双链RNA或含有双链体区域的RNA结合时被激活以进行自磷酸化。激活的PKR磷酸化真核起始因子2的α亚基，从而抑制蛋白质合成。PKR也被肝素激活，肝素是一种高度硫酸化的糖胺聚糖。我们已经使用生物物理方法来定义肝素激活PKR的机制。短至六糖的肝素与PKR强烈结合并激活自磷酸化。与双链RNA相反，肝素通过与激酶结构域结合来激活PKR。分析超离心测量支持热力学连接模型，其中肝素结合变构增强PKR二聚化，从而激活激酶。这些结果表明，PKR可以被小分子激活，并代表了一个可行的目标，为开发新的抗病毒药物。(C)2011爱思唯尔有限公司保留所有权利。
Protein kinase R (PKR) is an interferon-induced kinase that plays a pivotal role in the innate immunity pathway. PKR is activated to undergo autophosphorylation upon binding to double-stranded RNAs or RNAs that contain duplex regions. Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2, thereby inhibiting protein synthesis. PKR is also activated by heparin, a highly sulfated glycosaminoglycan. We have used biophysical methods to define the mechanism of PKR activation by heparin. Heparins as short as hexasaccharide bind strongly to PKR and activate autophosphorylation. In contrast to double-stranded RNA, heparin activates PKR by binding to the kinase domain. Analytical ultracentrifugation measurements support a thermodynamic linkage model where heparin binding allosterically enhances PKR dimerization, thereby activating the kinase. These results indicate that PKR can be activated by small molecules and represents a viable target for the development of novel antiviral agents. (C) 2011 Elsevier Ltd. All rights reserved.