Structural Basis of Protein Kinase R Autophosphorylation
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 feasib...
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| Veröffentlicht in: | Biochemistry (Easton) 2019-07, Vol.58 (27), p.2967-2977 |
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| container_issue | 27 |
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| container_title | Biochemistry (Easton) |
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| creator | Mayo, Christopher B Erlandsen, Heidi Mouser, David J Feinstein, Aaron G Robinson, Victoria L May, Eric R Cole, James L |
| description | 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. |
| doi_str_mv | 10.1021/acs.biochem.9b00161 |
| format | Article |
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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. 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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.</description><subject>Crystallography, X-Ray</subject><subject>dimerization</subject><subject>double-stranded RNA</subject><subject>eIF-2 Kinase - chemistry</subject><subject>geometry</subject><subject>Humans</subject><subject>immune response</subject><subject>innate immunity</subject><subject>molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>mutational analysis</subject><subject>Phosphorylation</subject><subject>Protein Conformation</subject><subject>Protein Domains</subject><subject>protein kinases</subject><subject>Protein Multimerization</subject><subject>protein phosphorylation</subject><subject>protein subunits</subject><subject>simulation models</subject><issn>0006-2960</issn><issn>1520-4995</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtLAzEUhYMotlZ_gSCzdDPtzWMe2Qi1-MKC4mMdMpmMTZlOajIj9N-b0lF0o4sQcvOdw733IHSKYYyB4IlUflwYqxZ6NeYFAE7xHhrihEDMOE_20RAA0pjwFAboyPtleDLI2CEaUExYyggfovy5dZ1qOyfr6FJ64yNbRY_Otto00b1ppNfRUzTtWrteWB-O29SyNbY5RgeVrL0-6e8Rer2-epndxvOHm7vZdB5LluVtzMoCK14oTFRRlUXCJdOqzDVgnReUMl6FekpohXPGMsmIUrgkQGhQcUiAjtDFznfdFStdKt20oVexdmYl3UZYacTvn8YsxJv9EGmKE855MDjvDZx977Rvxcp4petaNtp2XhAKYWVJDvA_ShJIGc0YDSjdocpZ752uvjvCILbxiBCP6OMRfTxBdfZzmG_NVx4BmOyArXppO9eE3f5p-QmIyZ8q</recordid><startdate>20190709</startdate><enddate>20190709</enddate><creator>Mayo, Christopher B</creator><creator>Erlandsen, Heidi</creator><creator>Mouser, David J</creator><creator>Feinstein, Aaron G</creator><creator>Robinson, Victoria L</creator><creator>May, Eric R</creator><creator>Cole, James L</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3838-6394</orcidid><orcidid>https://orcid.org/0000-0002-9028-8364</orcidid><orcidid>https://orcid.org/0000-0001-8826-1990</orcidid></search><sort><creationdate>20190709</creationdate><title>Structural Basis of Protein Kinase R Autophosphorylation</title><author>Mayo, Christopher B ; Erlandsen, Heidi ; Mouser, David J ; Feinstein, Aaron G ; Robinson, Victoria L ; May, Eric R ; Cole, James L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-4db1c9bc12cbfdb59a4ecd8e01e8b3349fcbf623f18447a42cc1d20231c990503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Crystallography, X-Ray</topic><topic>dimerization</topic><topic>double-stranded RNA</topic><topic>eIF-2 Kinase - chemistry</topic><topic>geometry</topic><topic>Humans</topic><topic>immune response</topic><topic>innate immunity</topic><topic>molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>mutational analysis</topic><topic>Phosphorylation</topic><topic>Protein Conformation</topic><topic>Protein Domains</topic><topic>protein kinases</topic><topic>Protein Multimerization</topic><topic>protein phosphorylation</topic><topic>protein subunits</topic><topic>simulation models</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mayo, Christopher B</creatorcontrib><creatorcontrib>Erlandsen, Heidi</creatorcontrib><creatorcontrib>Mouser, David J</creatorcontrib><creatorcontrib>Feinstein, Aaron G</creatorcontrib><creatorcontrib>Robinson, Victoria L</creatorcontrib><creatorcontrib>May, Eric R</creatorcontrib><creatorcontrib>Cole, James L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mayo, Christopher B</au><au>Erlandsen, Heidi</au><au>Mouser, David J</au><au>Feinstein, Aaron G</au><au>Robinson, Victoria L</au><au>May, Eric R</au><au>Cole, James L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Basis of Protein Kinase R Autophosphorylation</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2019-07-09</date><risdate>2019</risdate><volume>58</volume><issue>27</issue><spage>2967</spage><epage>2977</epage><pages>2967-2977</pages><issn>0006-2960</issn><issn>1520-4995</issn><eissn>1520-4995</eissn><abstract>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. 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| subjects | Crystallography, X-Ray dimerization double-stranded RNA eIF-2 Kinase - chemistry geometry Humans immune response innate immunity molecular dynamics Molecular Dynamics Simulation mutational analysis Phosphorylation Protein Conformation Protein Domains protein kinases Protein Multimerization protein phosphorylation protein subunits simulation models |
| title | Structural Basis of Protein Kinase R Autophosphorylation |
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