Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorRice University-
Autor(es): dc.contributorMassachusetts Institute of Technology-
Autor(es): dc.contributorCity of Hope National Medical Center-
Autor(es): dc.contributorIndian Institute of Science Education and Research Kolkata-
Autor(es): dc.contributorUniversidade Estadual Paulista (Unesp)-
Autor(es): dc.creatorOliveira Junior, Antonio B.-
Autor(es): dc.creatorLin, Xingcheng [UNESP]-
Autor(es): dc.creatorKulkarni, Prakash-
Autor(es): dc.creatorOnuchic, José N.-
Autor(es): dc.creatorRoy, Susmita-
Autor(es): dc.creatorLeite, Vitor B. P. [UNESP]-
Data de aceite: dc.date.accessioned2022-02-22T00:51:02Z-
Data de disponibilização: dc.date.available2022-02-22T00:51:02Z-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2020-12-31-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1021/acs.jctc.1c00027-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/207676-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/207676-
Descrição: dc.descriptionIntrinsically disordered proteins (IDPs) lack a rigid three-dimensional structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed energy landscape visualization method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, prostate-associated gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely, HIPK1 and CLK2, phosphorylate PAGE4, generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyperphosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield, and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool, especially to analyze the highly frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.-
Descrição: dc.descriptionCenter for Theoretical Biological Physics Rice University-
Descrição: dc.descriptionDepartment of Chemistry Massachusetts Institute of Technology-
Descrição: dc.descriptionDepartment of Medical Oncology and Therapeutics Research City of Hope National Medical Center-
Descrição: dc.descriptionDepartment of Chemical Sciences Indian Institute of Science Education and Research Kolkata-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista (UNESP)-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista (UNESP)-
Idioma: dc.languageen-
Relação: dc.relationJournal of Chemical Theory and Computation-
???dc.source???: dc.sourceScopus-
Título: dc.titleExploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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