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

Detalhes bibliográficos
Autor(a) principal: Oliveira Junior, Antonio B.
Data de Publicação: 2021
Outros Autores: Lin, Xingcheng [UNESP], Kulkarni, Prakash, Onuchic, José N., Roy, Susmita, Leite, Vitor B. P. [UNESP]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1021/acs.jctc.1c00027
http://hdl.handle.net/11449/207676
Resumo: Intrinsically 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.
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spelling Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional MechanismsIntrinsically 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.Center for Theoretical Biological Physics Rice UniversityDepartment of Chemistry Massachusetts Institute of TechnologyDepartment of Medical Oncology and Therapeutics Research City of Hope National Medical CenterDepartment of Chemical Sciences Indian Institute of Science Education and Research KolkataDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista (UNESP)Departamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista (UNESP)Rice UniversityMassachusetts Institute of TechnologyCity of Hope National Medical CenterIndian Institute of Science Education and Research KolkataUniversidade Estadual Paulista (Unesp)Oliveira Junior, Antonio B.Lin, Xingcheng [UNESP]Kulkarni, PrakashOnuchic, José N.Roy, SusmitaLeite, Vitor B. P. [UNESP]2021-06-25T10:59:11Z2021-06-25T10:59:11Z2021-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/acs.jctc.1c00027Journal of Chemical Theory and Computation.1549-96261549-9618http://hdl.handle.net/11449/20767610.1021/acs.jctc.1c000272-s2.0-85105083133Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Chemical Theory and Computationinfo:eu-repo/semantics/openAccess2021-10-23T17:45:47Zoai:repositorio.unesp.br:11449/207676Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-23T17:45:47Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
title Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
spellingShingle Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
Oliveira Junior, Antonio B.
title_short Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
title_full Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
title_fullStr Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
title_full_unstemmed Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
title_sort Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
author Oliveira Junior, Antonio B.
author_facet Oliveira Junior, Antonio B.
Lin, Xingcheng [UNESP]
Kulkarni, Prakash
Onuchic, José N.
Roy, Susmita
Leite, Vitor B. P. [UNESP]
author_role author
author2 Lin, Xingcheng [UNESP]
Kulkarni, Prakash
Onuchic, José N.
Roy, Susmita
Leite, Vitor B. P. [UNESP]
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Rice University
Massachusetts Institute of Technology
City of Hope National Medical Center
Indian Institute of Science Education and Research Kolkata
Universidade Estadual Paulista (Unesp)
dc.contributor.author.fl_str_mv Oliveira Junior, Antonio B.
Lin, Xingcheng [UNESP]
Kulkarni, Prakash
Onuchic, José N.
Roy, Susmita
Leite, Vitor B. P. [UNESP]
description Intrinsically 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.
publishDate 2021
dc.date.none.fl_str_mv 2021-06-25T10:59:11Z
2021-06-25T10:59:11Z
2021-01-01
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1021/acs.jctc.1c00027
Journal of Chemical Theory and Computation.
1549-9626
1549-9618
http://hdl.handle.net/11449/207676
10.1021/acs.jctc.1c00027
2-s2.0-85105083133
url http://dx.doi.org/10.1021/acs.jctc.1c00027
http://hdl.handle.net/11449/207676
identifier_str_mv Journal of Chemical Theory and Computation.
1549-9626
1549-9618
10.1021/acs.jctc.1c00027
2-s2.0-85105083133
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Journal of Chemical Theory and Computation
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv
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