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dc.contributor.authorDodson, CA
dc.contributor.authorYeoh, S
dc.contributor.authorHaq, T
dc.contributor.authorBayliss, R
dc.date.accessioned2018-08-06T11:09:49Z
dc.date.issued2013-07-02
dc.identifier282
dc.identifier.citationSCIENCE SIGNALING, 2013, 6
dc.identifier.issn1945-0877
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2269
dc.identifier.doi10.1126/scisignal.2003910
dc.description.abstractMany protein kinases catalyze their own activation by autophosphorylation. The mechanism of this is generally considered to be intermolecular and similar to that used in substrate phosphorylation. We derived the kinetic signatures of the four simplest autophosphorylation reactions and developed a test to determine the autoactivation mechanism of individual kinases. Whereas autophosphorylation of Nek7 and Plk4 occurred through an intermolecular mechanism, the kinases Aurora-A and Chk2 followed an intramolecular mechanism. Autophosphorylation of Aurora-A was accelerated in the presence of its protein activator TPX2. Nek9, the binding partner for Nek7, had a concentration-dependent effect such that low amounts enhanced autoactivation of Nek7 and high amounts were inhibitory. A structural model of Aurora-A undergoing autophosphorylation confirmed that an intramolecular mechanism is physically possible, and provided an explanation for how TPX2 could stimulate both autophosphorylation and substrate phosphorylation. The distinct mechanisms of autoactivation have consequences for cellular regulation because each molecule of a kinase that undergoes intramolecular autophosphorylation is activated individually, whereas the activity of kinases that undergo intermolecular autophosphorylation can be rapidly self-amplified in the cell. Local control of individual molecules, such as Aurora-A, may be particularly advantageous for a kinase with multiple, distinct cellular roles.
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.titleA Kinetic Test Characterizes Kinase Intramolecular and Intermolecular Autophosphorylation Mechanisms
dc.typeJournal Article
rioxxterms.versionofrecord10.1126/scisignal.2003910
rioxxterms.licenseref.startdate2013-07-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfSCIENCE SIGNALING
pubs.notesaffiliation: Dodson, CA (Reprint Author), Inst Canc Res, Div Struct Biol, 237 Fulham Rd, London SW3 6JB, England. Dodson, Charlotte A.; Bayliss, Richard, Inst Canc Res, Div Struct Biol, London SW3 6JB, England. Dodson, Charlotte A., Univ Oxford, Chem Res Lab, Oxford OX1 3TA, England. Yeoh, Sharon, Univ Leicester, Henry Wellcome Labs Struct Biol, Ctr Translat Therapeut, Leicester LE1 9HN, Leics, England. Haq, Tamanna; Bayliss, Richard, Univ Leicester, Henry Wellcome Labs Struct Biol, Dept Biochem, Leicester LE1 9HN, Leics, England. article-number: ra54 keywords-plus: ACTIVATION-LOOP AUTOPHOSPHORYLATION; MITOTIC SPINDLE FORMATION; AURORA-A; TYROSINE KINASE; DRUG DESIGN; PROTEIN; PHOSPHORYLATION; BINDING; NEK6; AUTOACTIVATION research-areas: Biochemistry & Molecular Biology; Cell Biology web-of-science-categories: Biochemistry & Molecular Biology; Cell Biology author-email: [email protected] [email protected] orcid-numbers: Bayliss, Richard/0000-0003-0604-2773 Dodson, Charlotte/0000-0002-8403-726X funding-acknowledgement: Cancer Research UK [C24461/A8032, C24461/A12772]; Royal Society University Research Fellowship; Cancer Research UK [12772] funding-text: This work was supported by grants to R.B. from Cancer Research UK (C24461/A8032 and C24461/A12772) and a Royal Society University Research Fellowship. number-of-cited-references: 33 times-cited: 22 usage-count-last-180-days: 2 usage-count-since-2013: 22 journal-iso: Sci. Signal. doc-delivery-number: 174ZL unique-id: ISI:000321197800004 da: 2018-08-06
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.volume6
pubs.embargo.termsNot known
dc.contributor.icrauthorDodson, Charlotteen
dc.contributor.icrauthorBayliss, Richarden


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