Structure and Function of the Protein Kinase R

'Monash Institute of Medical Research, Monash University, Melbourne,

Victoria 3168, Australia

[email protected]

1 Abbreviations 254

2 Introduction 254

3 Properties of PKR 255

3.1 Genetic Characterization 255

3.2 Protein Structure 256

4 PKR Activity 259

4.1 Kinase Activation 259

4.2 Activating Ligands 262

4.3 Inhibitors 264

4.4 Protein Substrates 265

5 Processes Regulated by PKR 268

5.1 Cell Differentiation and Development 268

5.2 Cell Signalling 270

5.3 Disease Processes 272

6 Conclusions 275

References 275

Abstract The protein kinase R (PKR) is an intracellular sensor of stress, exemplified by viral infection. Double-stranded (ds) RNA produced during viral replication activates PKR, which in turn arrests protein synthesis by phosphorylating the a subunit of the translation initiation factor eIF2. As well as dsRNA, two additional ligands, PACT and heparin, directly activate the kinase. These mediate the response of PKR to additional indirect stimuli, including bacterial lipopolysaccharides, ceramide and polyanionic molecules. This responsiveness to multiple stimuli advocates a broader role for PKR as a signalling molecule for diverse physiological stresses. Appropriately, a number of other protein substrates have been reported for PKR. These substrates support additional roles for PKR in the regulation of transcription and signal transduction in infected cells, as well as uninfected but diseased tissues, such as in tumorigenesis and neurodegenera-tive diseases. Finally, PKR plays a role in normal cell differentiation in platelet-derived growth factor signalling and in osteoblast-mediated calcification.

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