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Current Topics in Biochemical Research   Volumes    Volume 17 
Abstract
Molecular basis of the regulation of the double-stranded RNA-activated protein kinase PKR by the Src homology domain-containing adaptor protein Nck1
Afnan Abu-Thuraia, George Kefalas, Mohammed Selman, Nafisa Tasnim, Louise Larose
Pages: 31 - 44
Number of pages: 14
Current Topics in Biochemical Research
Volume 17 

Copyright © 2016 Research Trends. All rights reserved

ABSTRACT
 
Tight regulation of the double-stranded RNA-activated protein kinase PKR is critical for the maintenance of cellular homeostasis due to its potent inhibitory role on general translation. However, the endogenous molecular mechanisms that regulate PKR are still largely unknown. We have previously identified the Src homology domain-containing adaptor protein Nck1 as a novel regulator of PKR through its interaction with PKR. In this study, we report that the negative control of PKR by Nck1 is reversible by showing that significant levels of dsRNA override Nck1 binding and inhibition of PKR. Biochemical approaches reveal that Nck1 must be in its full length form to interact with and modulate PKR activation. However, both binding and regulation appear to occur independently of the classical binding function of Nck1 Src-homology domains and the interaction between the two proteins involves two binding sites for Nck1 on PKR. Furthermore, we found that the dissociation of Nck1 from PKR in the presence of significant levels of dsRNA results from the activation of PKR catalytic activity rather than competition by dsRNA or change in PKR conformation. Finally, we provide strong evidence that Nck1 is phosphorylated by PKR in a cellular context. Hence, Nck1 not only buffers PKR activation, but it also appears to be a substrate of PKR. Therefore, we propose that PKR-mediated Nck1 phosphorylation is part of the mechanism that promotes Nck1 dissociation from PKR and leads to efficient activation of PKR.
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