Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms
| Autor: | Prakash Kulkarni, Vitor B. P. Leite, Susmita Roy, Xingcheng Lin, José N. Onuchic, Antonio B Oliveira Junior |
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| Přispěvatelé: | Rice University, Massachusetts Institute of Technology, City of Hope National Medical Center, Indian Institute of Science Education and Research Kolkata, Universidade Estadual Paulista (Unesp) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
education.field_of_study
Sequence Homology Amino Acid 010304 chemical physics Protein Conformation Chemistry Population Reproducibility of Results Energy landscape Computational biology Intrinsically disordered proteins 01 natural sciences Computer Science Applications Intrinsically Disordered Proteins Phase space Population Distributions Transcriptional Coactivator 0103 physical sciences Protein Isoforms Amino Acid Sequence Phosphorylation Physical and Theoretical Chemistry education Conformational ensembles Energy (signal processing) |
| Zdroj: | Scopus Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP |
| Popis: | Made available in DSpace on 2021-06-25T10:59:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 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. Center for Theoretical Biological Physics Rice University Department of Chemistry Massachusetts Institute of Technology Department of Medical Oncology and Therapeutics Research City of Hope National Medical Center Department of Chemical Sciences Indian Institute of Science Education and Research Kolkata Departamento 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) |
| Databáze: | OpenAIRE |
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