Structural Basis of Protein Kinase R Autophosphorylation
| Autor: | Christopher B. Mayo, Heidi Erlandsen, David J. Mouser, Aaron G. Feinstein, Victoria L. Robinson, Eric R. May, James L. Cole |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
viruses digestive oral and skin physiology biochemical phenomena metabolism and nutrition Molecular Dynamics Simulation Crystallography X-Ray environment and public health Biochemistry Article enzymes and coenzymes (carbohydrates) eIF-2 Kinase Protein Domains Humans Phosphorylation Protein Multimerization |
| Zdroj: | Biochemistry |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.9b00161 |
| Popis: | The RNA-activated protein kinase, PKR, is a key mediator of the innate immunity response to viral infection. Viral double-stranded RNAs induce PKR dimerization and autophosphorylation. The PKR kinase domain forms a back-to-back dimer. However, intermolecular ( trans) autophosphorylation is not feasible in this arrangement. We have obtained PKR kinase structures that resolves this dilemma. The kinase protomers interact via the known back-to-back interface as well as a front-to-front interface that is formed by exchange of activation segments. Mutational analysis of the front-to-front interface support a functional role in PKR activation. Molecular dynamics simulations reveal that the activation segment is highly dynamic in the front-to-front dimer and can adopt conformations conducive to phosphoryl transfer. We propose a mechanism where back-to-back dimerization induces a conformational change that activates PKR to phosphorylate a "substrate" kinase docked in a front-to-front geometry. This mechanism may be relevant to related kinases that phosphorylate the eukaryotic initiation factor eIF2α. |
| Databáze: | OpenAIRE |
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