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

Autor(es)

Oliveira, Jr., Antonio B. ^[1] ; Lin, Xingcheng ^[2] ; Kulkarni, Prakash ^[3] ; Onuchic, Jose N. ^[1] ; Roy, Susmita ^[4] ; Leite, Vitor B. P. ^[5]

Afiliação do(s) autor(es)

^[1] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 - USA

^[2] MIT, Dept Chem, Cambridge, MA 02139 - USA

^[3] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 - USA

^[4] Indian Inst Sci Educ & Res Kolkata, Dept Chem Sci, Mohanpur 741246, W Bengal - India

^[5] Univ Estadual Paulista UNESP, Inst Biociencias Letras & Cincias Exatas, Dept Fis, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL THEORY AND COMPUTATION; v. 17, n. 5, p. 3178-3187, MAY 11 2021.
• Citações Web of Science: 0

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. (AU)

• Processo FAPESP: 16/01343-7 - ICTP Instituto Sul-Americano para Física Fundamental: um centro regional para física teórica
• Beneficiário: Nathan Jacob Berkovits
• Modalidade de apoio: Auxílio à Pesquisa - Projetos Especiais
• Processo FAPESP: 19/22540-3 - Estudos de relevo de superfícies de energia de macromoléculas biológicas
• Beneficiário: Vitor Barbanti Pereira Leite
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/18668-1 - Visualização do relevo de superfícies de energia de macromoléculas biológicas
• Beneficiário: Vitor Barbanti Pereira Leite
• Modalidade de apoio: Bolsas no Exterior - Pesquisa