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dc.contributor.authorCrabtree, Michaelen
dc.contributor.authorBorcherds, Wadeen
dc.contributor.authorPoosapati, Anushaen
dc.contributor.authorShammas, Sarah Len
dc.contributor.authorDaughdrill, Gary Wen
dc.contributor.authorClarke, Janeen
dc.date.accessioned2018-03-26T07:43:36Z
dc.date.available2018-03-26T07:43:36Z
dc.date.issued2017-05en
dc.identifier.issn0006-2960
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/274312
dc.description.abstractAppropriate integration of cellular signals requires a delicate balance of ligand-target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity. In both cases, changes in affinity were due to alterations in dissociation, not association, rate constants, which is inconsistent with conformational selection mechanisms. We conclude that, contrary to previous suggestions, helix-flanking prolines do not regulate affinity by modulating the rate of complex formation. Instead, they influence binding affinities by controlling the lifetime of the bound complex.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectEscherichia colien
dc.subjectHistone-Lysine N-Methyltransferaseen
dc.subjectProlineen
dc.subjectMembrane Proteinsen
dc.subjectPhosphoproteinsen
dc.subjectRecombinant Proteinsen
dc.subjectCloning, Molecularen
dc.subjectSequence Alignmenten
dc.subjectGene Expressionen
dc.subjectBinding Sitesen
dc.subjectAmino Acid Sequenceen
dc.subjectConserved Sequenceen
dc.subjectProtein Bindingen
dc.subjectProtein Foldingen
dc.subjectSequence Homology, Amino Aciden
dc.subjectMutationen
dc.subjectModels, Molecularen
dc.subjectTumor Suppressor Protein p53en
dc.subjectMyeloid-Lymphoid Leukemia Proteinen
dc.subjectProtein Interaction Domains and Motifsen
dc.subjectIntrinsically Disordered Proteinsen
dc.subjectProtein Conformation, alpha-Helicalen
dc.titleConserved Helix-Flanking Prolines Modulate Intrinsically Disordered Protein:Target Affinity by Altering the Lifetime of the Bound Complex.en
dc.typeArticle
prism.endingPage2384
prism.issueIdentifier18en
prism.publicationDate2017en
prism.publicationNameBiochemistryen
prism.startingPage2379
prism.volume56en
dc.identifier.doi10.17863/CAM.21435
dcterms.dateAccepted2017-04-20en
rioxxterms.versionofrecord10.1021/acs.biochem.7b00179en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-05en
dc.contributor.orcidCrabtree, Michael [0000-0003-1466-4011]
dc.contributor.orcidClarke, Jane [0000-0002-7921-900X]
dc.identifier.eissn1520-4995
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (095195/Z/10/Z)
rioxxterms.freetoread.startdate2018-04-20


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