Heparin Activates PKR by Inducing Dimerization

JOURNAL OF MOLECULAR BIOLOGY

卷:413

Article

Anderson, Eric¹  Pierre-Louis, Willythssa S.¹  Wong, C. Jason¹  Lary, Jeffrey W.²  Cole, James L.^1,2,3 

[1] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA

[2] Univ Connecticut, Natl Analyt Ultracentrifugat Facil, Storrs, CT 06269 USA

[3] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA

关键词: analytical ultracentrifugation;    drug discovery;    innate immunity;    protein kinase R;   

DOI  :  10.1016/j.jmb.2011.09.025

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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