PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer
學年 107
學期 1
出版(發表)日期 2018-08-03
作品名稱 PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer
著者 Xingcheng Lin; Susmita Roy; Mohit Kumar Jolly; Federico Bocci; Nicholas P.Schafer; Min-Yeh Tsai; Yihong Chen; Yanan He; Alexander Grishaev; Keith Weninger; John Orban; Prakash Kulkarni; Govindan Rangarajan; Herbert Levine; José N.Onuchic
著錄名稱、卷期、頁數 Journal of Molecular Biology, 430 (16), 2422
摘要 Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein implicated in prostate cancer. Thestress-response kinase homeodomain-interacting protein kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with activator protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity. In contrast, hyperphosphorylation of PAGE4 by CDC-like kinase 2 (CLK2) attenuates this interaction with AP-1. Small-angleX-ray scattering and single-molecule fluorescence resonance energy transfer measurements have shown that PAGE4 expands upon hyperphosphorylation and that this expansion is localized to its N-terminal half. To understand the interactions underlying this structural transition, we performed molecular dynamics simulations using Atomistic AWSEM, a multi-scale molecular model that combines atomistic and coarse-grained simulation approaches. Our simulations show that electrostatic interactions drive transient formation of an N-terminal loop, the destabilization of which accounts for the dramatic change in size upon hyperphosphorylation. Phosphorylation also changes the preference of secondary structure formation of the PAGE4 ensemble, which leads to a transition between states that display different degrees of disorder. Finally, we construct a mechanism-based mathematical model that allows us to capture the interactions ofdifferent phosphoforms of PAGE4 with AP-1 and its downstream target, the androgen receptor (AR)—a key therapeutic target in prostate cancer. Our model predicts intracellular oscillatory dynamics of HIPK1-PAGE4, CLK2-PAGE4, and AR activity, indicating phenotypic heterogeneity in an isogenic cell population. Thus, conformational switching of PAGE4 may potentially affect the efficiency of therapeutically targeting AR activity.
關鍵字 intrinsically disordered protein;PAGE4;AWSEM;order–disorder transition;non-genetic heterogeneity
語言 en_US
ISSN 0022-2836
期刊性質 國外
收錄於 SCI
通訊作者 J. N. Onuchic
國別 USA
出版型式 ,電子版,紙本

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