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From Proteopedia
Protein Kinase R
Abstract
One mechanism against viral infection preventing viral propagation by inhibiting cellular protein synthesis. The protein kinase R (PKR) is an several enzymes involved in cellular immunity against viral infection. PKR is composed of two domains: two double stranded RNA (dsRNA) binding domains and a kinase domain (KD). The crystal structure of the PKR KD is bound to its substrate, initiation factor eIF2α revealing that each KD is composed of N-terminal (N-lobe) and C-terminal lobes (C-lobe). The active site lies between these two lobes, which also contains an ATP. The two N-lobes of each PKR KD interact to form a dimer whereas the C-lobe is bound to eIF2α composed of an S1 domain and a helical domain. Upon viral infection, PKR senses the dsRNA inserted by the virus, and is dimerized and activated. The active PKR molecule then binds to eIF2α, causing a conformational change in eIF2α, bringing the helix insert containing Ser51 (phospho-acceptor residue) closer to the ATP. The γ phosphate of ATP is then transferred to the Ser51, and the phosphorylated eIF2α inhibits protein synthesis in infected cells. Such fundamental insights into the mechanisms of substrate recognition and phosphorylation by PKR will help design a small molecule that will activate PKR, leading to improved immunity against multiple viral infections. In addition, the mechanism of PKR function may be applied to cancer therapy due to its role in controlling cell differentiation.
Viral Defense against PKR Function
Viruses spread throughout the body by invading cells and hijacking the protein production machinery of the cell in order to replicate. However, there are several defense mechanisms used to counter viral infection. One is protein kinase R (PKR). In an uninfected cell, PKR exists as an inactive molecule. However, the presence of viral RNA triggers the PKR to form an active dimer. The active PKR then binds to an initiation factor eIF2α and transfers a phosphate from an ATP to the eIF2α, thereby inhibiting cellular and viral protein synthesis.
Viruses have evolved several mechanisms to subvert the PKR function (Figure 1). The VAI (Viral Associated I) RNA of adenovirus serves to prevent the dimerization and activation of PKR and inhibit the anti-viral response. Influenza virus p58IPK inhibits the activation of PKR. On the other hand, the smallpox virus K3L protein is a molecular mimic of eIF2α, acting as a competitive inhibitor and inhibits the phosphorylation reaction. Therefore fundamental understanding of this specific interaction between eIF2α and PKR and how viruses interfere with the reaction between the two is of paramount importance in developing anti-viral drugs.
