Deciphering the structural basis of eukaryotic protein kinase regulation
Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essen...
Gespeichert in:
Veröffentlicht in: | PLoS biology 2013-10, Vol.11 (10), p.e1001680 |
---|---|
Hauptverfasser: | , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
container_issue | 10 |
container_start_page | e1001680 |
container_title | PLoS biology |
container_volume | 11 |
creator | Meharena, Hiruy S Chang, Philip Keshwani, Malik M Oruganty, Krishnadev Nene, Aishwarya K Kannan, Natarajan Taylor, Susan S Kornev, Alexandr P |
description | Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors. |
doi_str_mv | 10.1371/journal.pbio.1001680 |
format | Article |
fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1458892255</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A350977160</galeid><doaj_id>oai_doaj_org_article_673b41e94bd94b768a3f58fd8f8b984b</doaj_id><sourcerecordid>A350977160</sourcerecordid><originalsourceid>FETCH-LOGICAL-c694t-d7533d4286af13c7c06673c52ffaa62faed8df48b85c57e308e609857c9a1c653</originalsourceid><addsrcrecordid>eNqVkktvEzEUhUcIREvhHyAYqSsWCX4_NkhVeTRSRSVeW8vjsSdOJ_bI9iD49zgkrZodLCxb9nfP9T06TfMSgiXEHL7dxDkFPS6nzsclBAAyAR41p5ASuuBC0McPzifNs5w3ACAkkXjanCACCYYYnzZX763x09omH4a2rG2bS5pNmZMe205nn9voWjvf6vQ7Fm_aKcVifWhvfdDZtskO86iLj-F588TpMdsXh_2s-f7xw7fLq8X1zafV5cX1wjBJyqLnFOOeIMG0g9hwAxjj2FDknNYMOW170TsiOkEN5RYDYRmQgnIjNTSM4rPm9V53GmNWBxOygoQKIRGiO2K1J_qoN2pKfls_r6L26u9FTIPSqc4yWlVbdwRaSbq-Ls6Exo4K1wsnOilIV7XeHbrN3db2xoZSnTkSPX4Jfq2G-FNhLjnAqAqc7wUGXfv54GLFzNZnoy4wBZJzyECl3hxRJoZif5VBzzmr1dcv_8F-_nf25scxS_asSTHnZN39lBCoXeLuzFa7xKlD4mrZq4cO3RfdRQz_Aa6S0oc</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Deciphering the structural basis of eukaryotic protein kinase regulation</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Public Library of Science (PLoS)</source><creator>Meharena, Hiruy S ; Chang, Philip ; Keshwani, Malik M ; Oruganty, Krishnadev ; Nene, Aishwarya K ; Kannan, Natarajan ; Taylor, Susan S ; Kornev, Alexandr P</creator><creatorcontrib>Meharena, Hiruy S ; Chang, Philip ; Keshwani, Malik M ; Oruganty, Krishnadev ; Nene, Aishwarya K ; Kannan, Natarajan ; Taylor, Susan S ; Kornev, Alexandr P</creatorcontrib><description>Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.1001680</identifier><identifier>PMID: 24143133</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Motifs ; Amino Acids - metabolism ; Biocatalysis ; Databases, Protein ; Diabetes ; Enzyme Activation ; Eukaryota - enzymology ; Experiments ; Health aspects ; Hydrophobic and Hydrophilic Interactions ; Kinases ; Models, Molecular ; Phosphorylation ; Physiological aspects ; Protein binding ; Protein kinases ; Protein Kinases - chemistry ; Protein Kinases - metabolism ; Sequence Alignment ; Structure-Activity Relationship</subject><ispartof>PLoS biology, 2013-10, Vol.11 (10), p.e1001680</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Meharena et al 2013 Meharena et al</rights><rights>2013 Meharena et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Meharena HS, Chang P, Keshwani MM, Oruganty K, Nene AK, et al. (2013) Deciphering the Structural Basis of Eukaryotic Protein Kinase Regulation. PLoS Biol 11(10): e1001680. doi:10.1371/journal.pbio.1001680</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c694t-d7533d4286af13c7c06673c52ffaa62faed8df48b85c57e308e609857c9a1c653</citedby><cites>FETCH-LOGICAL-c694t-d7533d4286af13c7c06673c52ffaa62faed8df48b85c57e308e609857c9a1c653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797032/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797032/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24143133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meharena, Hiruy S</creatorcontrib><creatorcontrib>Chang, Philip</creatorcontrib><creatorcontrib>Keshwani, Malik M</creatorcontrib><creatorcontrib>Oruganty, Krishnadev</creatorcontrib><creatorcontrib>Nene, Aishwarya K</creatorcontrib><creatorcontrib>Kannan, Natarajan</creatorcontrib><creatorcontrib>Taylor, Susan S</creatorcontrib><creatorcontrib>Kornev, Alexandr P</creatorcontrib><title>Deciphering the structural basis of eukaryotic protein kinase regulation</title><title>PLoS biology</title><addtitle>PLoS Biol</addtitle><description>Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors.</description><subject>Amino Acid Motifs</subject><subject>Amino Acids - metabolism</subject><subject>Biocatalysis</subject><subject>Databases, Protein</subject><subject>Diabetes</subject><subject>Enzyme Activation</subject><subject>Eukaryota - enzymology</subject><subject>Experiments</subject><subject>Health aspects</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Kinases</subject><subject>Models, Molecular</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein binding</subject><subject>Protein kinases</subject><subject>Protein Kinases - chemistry</subject><subject>Protein Kinases - metabolism</subject><subject>Sequence Alignment</subject><subject>Structure-Activity Relationship</subject><issn>1545-7885</issn><issn>1544-9173</issn><issn>1545-7885</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkktvEzEUhUcIREvhHyAYqSsWCX4_NkhVeTRSRSVeW8vjsSdOJ_bI9iD49zgkrZodLCxb9nfP9T06TfMSgiXEHL7dxDkFPS6nzsclBAAyAR41p5ASuuBC0McPzifNs5w3ACAkkXjanCACCYYYnzZX763x09omH4a2rG2bS5pNmZMe205nn9voWjvf6vQ7Fm_aKcVifWhvfdDZtskO86iLj-F588TpMdsXh_2s-f7xw7fLq8X1zafV5cX1wjBJyqLnFOOeIMG0g9hwAxjj2FDknNYMOW170TsiOkEN5RYDYRmQgnIjNTSM4rPm9V53GmNWBxOygoQKIRGiO2K1J_qoN2pKfls_r6L26u9FTIPSqc4yWlVbdwRaSbq-Ls6Exo4K1wsnOilIV7XeHbrN3db2xoZSnTkSPX4Jfq2G-FNhLjnAqAqc7wUGXfv54GLFzNZnoy4wBZJzyECl3hxRJoZif5VBzzmr1dcv_8F-_nf25scxS_asSTHnZN39lBCoXeLuzFa7xKlD4mrZq4cO3RfdRQz_Aa6S0oc</recordid><startdate>20131001</startdate><enddate>20131001</enddate><creator>Meharena, Hiruy S</creator><creator>Chang, Philip</creator><creator>Keshwani, Malik M</creator><creator>Oruganty, Krishnadev</creator><creator>Nene, Aishwarya K</creator><creator>Kannan, Natarajan</creator><creator>Taylor, Susan S</creator><creator>Kornev, Alexandr P</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>5PM</scope><scope>DOA</scope><scope>CZG</scope></search><sort><creationdate>20131001</creationdate><title>Deciphering the structural basis of eukaryotic protein kinase regulation</title><author>Meharena, Hiruy S ; Chang, Philip ; Keshwani, Malik M ; Oruganty, Krishnadev ; Nene, Aishwarya K ; Kannan, Natarajan ; Taylor, Susan S ; Kornev, Alexandr P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c694t-d7533d4286af13c7c06673c52ffaa62faed8df48b85c57e308e609857c9a1c653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Motifs</topic><topic>Amino Acids - metabolism</topic><topic>Biocatalysis</topic><topic>Databases, Protein</topic><topic>Diabetes</topic><topic>Enzyme Activation</topic><topic>Eukaryota - enzymology</topic><topic>Experiments</topic><topic>Health aspects</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Kinases</topic><topic>Models, Molecular</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein binding</topic><topic>Protein kinases</topic><topic>Protein Kinases - chemistry</topic><topic>Protein Kinases - metabolism</topic><topic>Sequence Alignment</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meharena, Hiruy S</creatorcontrib><creatorcontrib>Chang, Philip</creatorcontrib><creatorcontrib>Keshwani, Malik M</creatorcontrib><creatorcontrib>Oruganty, Krishnadev</creatorcontrib><creatorcontrib>Nene, Aishwarya K</creatorcontrib><creatorcontrib>Kannan, Natarajan</creatorcontrib><creatorcontrib>Taylor, Susan S</creatorcontrib><creatorcontrib>Kornev, Alexandr P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Biology</collection><jtitle>PLoS biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meharena, Hiruy S</au><au>Chang, Philip</au><au>Keshwani, Malik M</au><au>Oruganty, Krishnadev</au><au>Nene, Aishwarya K</au><au>Kannan, Natarajan</au><au>Taylor, Susan S</au><au>Kornev, Alexandr P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deciphering the structural basis of eukaryotic protein kinase regulation</atitle><jtitle>PLoS biology</jtitle><addtitle>PLoS Biol</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>11</volume><issue>10</issue><spage>e1001680</spage><pages>e1001680-</pages><issn>1545-7885</issn><issn>1544-9173</issn><eissn>1545-7885</eissn><abstract>Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24143133</pmid><doi>10.1371/journal.pbio.1001680</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1545-7885 |
ispartof | PLoS biology, 2013-10, Vol.11 (10), p.e1001680 |
issn | 1545-7885 1544-9173 1545-7885 |
language | eng |
recordid | cdi_plos_journals_1458892255 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
subjects | Amino Acid Motifs Amino Acids - metabolism Biocatalysis Databases, Protein Diabetes Enzyme Activation Eukaryota - enzymology Experiments Health aspects Hydrophobic and Hydrophilic Interactions Kinases Models, Molecular Phosphorylation Physiological aspects Protein binding Protein kinases Protein Kinases - chemistry Protein Kinases - metabolism Sequence Alignment Structure-Activity Relationship |
title | Deciphering the structural basis of eukaryotic protein kinase regulation |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-17T08%3A09%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Deciphering%20the%20structural%20basis%20of%20eukaryotic%20protein%20kinase%20regulation&rft.jtitle=PLoS%20biology&rft.au=Meharena,%20Hiruy%20S&rft.date=2013-10-01&rft.volume=11&rft.issue=10&rft.spage=e1001680&rft.pages=e1001680-&rft.issn=1545-7885&rft.eissn=1545-7885&rft_id=info:doi/10.1371/journal.pbio.1001680&rft_dat=%3Cgale_plos_%3EA350977160%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/24143133&rft_galeid=A350977160&rft_doaj_id=oai_doaj_org_article_673b41e94bd94b768a3f58fd8f8b984b&rfr_iscdi=true |