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Molecular Basis for Ser/Thr Specificity in PKA Signaling

dc.date.accessioned2020-07-02T09:41:53Z
dc.date.available2020-07-02T09:41:53Z
dc.date.issued2020-06-25
dc.identifierdoi:10.17170/kobra-202007011392
dc.identifier.urihttp://hdl.handle.net/123456789/11620
dc.description.sponsorshipGefördert durch den Publikationsfonds der Universität Kasselger
dc.language.isoengeng
dc.rightsNamensnennung 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectcAMP-dependent protein kinaseeng
dc.subjectPKAeng
dc.subjectcAMP signalingeng
dc.subjectprotein kinaseseng
dc.subjectkinase functioneng
dc.subjectphosphorylationeng
dc.subjectsubstrate specificityeng
dc.subjectSer/Thr specificityeng
dc.subjectsurface plasmon resonanceeng
dc.subject.ddc540
dc.titleMolecular Basis for Ser/Thr Specificity in PKA Signalingeng
dc.typeAufsatz
dcterms.abstractcAMP-dependent protein kinase (PKA) is the major receptor of the second messenger cAMP and a prototype for Ser/Thr-specific protein kinases. Although PKA strongly prefers serine over threonine substrates, little is known about the molecular basis of this substrate specificity. We employ classical enzyme kinetics and a surface plasmon resonance (SPR)-based method to analyze each step of the kinase reaction. In the absence of divalent metal ions and nucleotides, PKA binds serine (PKS) and threonine (PKT) substrates, derived from the heat-stable protein kinase inhibitor (PKI), with similar affinities. However, in the presence of metal ions and adenine nucleotides, the Michaelis complex for PKT is unstable. PKA phosphorylates PKT with a higher turnover due to a faster dissociation of the product complex. Thus, threonine substrates are not necessarily poor substrates of PKA. Mutation of the DFG+1 phenylalanine to β-branched amino acids increases the catalytic efficiency of PKA for a threonine peptide substrate up to 200-fold. The PKA Cα mutant F187V forms a stable Michaelis complex with PKT and shows no preference for serine versus threonine substrates. Disease-associated mutations of the DFG+1 position in other protein kinases underline the importance of substrate specificity for keeping signaling pathways segregated and precisely regulated.eng
dcterms.accessRightsopen access
dcterms.creatorKnape, Matthias Joseph
dcterms.creatorWallbott, Maximilian
dcterms.creatorBurghardt, Nicole C. G.
dcterms.creatorBertinetti, Daniela
dcterms.creatorHornung, Jan
dcterms.creatorSchmidt, Sven H.
dcterms.creatorLorenz, Robin
dcterms.creatorHerberg, Friedrich Wilhelm
dc.relation.doidoi:10.3390/cells9061548
dc.subject.swdProteinkinase Ager
dc.subject.swdProteinkinasenger
dc.subject.swdPhosphorylierungger
dc.type.versionpublishedVersion
dcterms.source.identifierEISSN 2073-4409
dcterms.source.issueIssue 6
dcterms.source.journalCellseng
dcterms.source.pageinfo1548
dcterms.source.volumeVolume 9
kup.iskupfalse


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