Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

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dc.citation.articleNumber77en_US
dc.citation.issueNumber2en_US
dc.citation.journalTitleBiomoleculesen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorLin, Xingchengen_US
dc.contributor.authorKulkarni, Prakashen_US
dc.contributor.authorBocci, Federicoen_US
dc.contributor.authorSchafer, Nicholas P.en_US
dc.contributor.authorRoy, Susmitaen_US
dc.contributor.authorTsai, Min-Yehen_US
dc.contributor.authorHe, Yananen_US
dc.contributor.authorChen, Yihongen_US
dc.contributor.authorRajagopalan, Krithikaen_US
dc.contributor.authorMooney, Steven M.en_US
dc.contributor.authorZeng, Yuen_US
dc.contributor.authorWeninger, Keithen_US
dc.contributor.authorGrishaev, Alexen_US
dc.contributor.authorOnuchic, José Nelsonen_US
dc.contributor.authorLevine, Herberten_US
dc.contributor.authorWolynes, Peter G.en_US
dc.contributor.authorSalgia, Ravien_US
dc.contributor.authorRangarajan, Govindanen_US
dc.contributor.authorUversky, Vladimiren_US
dc.contributor.authorOrban, Johnen_US
dc.contributor.authorJolly, Mohit Kumaren_US
dc.date.accessioned2019-12-05T18:52:41Zen_US
dc.date.available2019-12-05T18:52:41Zen_US
dc.date.issued2019en_US
dc.description.abstractFolded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.en_US
dc.identifier.citationLin, Xingcheng, Kulkarni, Prakash, Bocci, Federico, et al.. "Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level." <i>Biomolecules,</i> 9, no. 2 (2019) MDPI: https://doi.org/10.3390/biom9020077.en_US
dc.identifier.digitalbiomolecules-09-00077en_US
dc.identifier.doihttps://doi.org/10.3390/biom9020077en_US
dc.identifier.urihttps://hdl.handle.net/1911/107782en_US
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.rightsThis is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citeden_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordPAGE4en_US
dc.subject.keywordintrinsically disordered proteinsen_US
dc.subject.keywordconformational plasticityen_US
dc.subject.keywordorder–disorder transitionen_US
dc.subject.keywordphosphorylationen_US
dc.titleStructural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Levelen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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