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dc.contributor.authorCrabtree, Michaelen
dc.contributor.authorBorcherds, Wen
dc.contributor.authorPoospati, Aen
dc.contributor.authorShammas, SLen
dc.contributor.authorDaughdrill, GWen
dc.contributor.authorClarke, Janeen
dc.date.accessioned2017-04-21T11:35:14Z
dc.date.available2017-04-21T11:35:14Z
dc.date.issued2047-05-09en
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263749
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.description.sponsorshipNational Institutes of Health (2R01CA14124406-A1 and 1R01GM115556-01A1).
dc.language.isoenen
dc.publisherAmerican Chemical Society
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleConserved Helix-Flanking Prolines Modulate Intrinsically Disordered Protein:Target Affinity by Altering the Lifetime of the Bound Complexen
dc.typeArticle
prism.endingPage2384
prism.issueIdentifier18en
prism.publicationDate2047en
prism.publicationNameBiochemistryen
prism.startingPage2379
prism.volume56en
dc.identifier.doi10.17863/CAM.9119
dcterms.dateAccepted2017-04-13en
rioxxterms.versionofrecord10.1021/acs.biochem.7b00179en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2047-05-09en
dc.contributor.orcidCrabtree, Michael [0000-0003-1466-4011]
dc.contributor.orcidClarke, Jane [0000-0002-7921-900X]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (1348064)
pubs.funder-project-idWellcome Trust (095195/Z/10/Z)
cam.issuedOnline2017-04-20en
dc.identifier.urlhttps://pubs.acs.org/doi/10.1021/acs.biochem.7b00179en
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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International