PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer. Issue 16 (3rd August 2018)

• Record Type: Journal Article
• Authors: Lin, Xingcheng; Roy, Susmita; Jolly, Mohit Kumar; Bocci, Federico; Schafer, Nicholas P.; Tsai, Min-Yeh; Chen, Yihong; He, Yanan; Grishaev, Alexander; Weninger, Keith; Orban, John; Kulkarni, Prakash; Rangarajan, Govindan; Levine, Herbert; Onuchic, José N.
• Is Part Of: Journal of molecular biology. Volume 430:Issue 16(2018)
• Page Start: 2422
• Page End: 2438
• Publication Date: 2018-08-03
• Subjects: intrinsically disordered protein -- PAGE4 -- AWSEM -- order–disorder transition -- non-genetic heterogeneity; IDPs intrinsically disordered proteins -- PAGE4 prostate-associated gene 4 -- PCa prostate cancer -- AP-1 activator protein-1 -- AR androgen receptor -- HIPK1 homeodomain-interacting protein kinase 1 -- CLK2 CDC-like kinase 2 -- SAXS small-angle X-ray scattering -- smFRET single-molecule fluorescence resonance energy transfer -- MD molecular dynamics -- AWSEM Associative memory, Water mediated, Structure and Energy Model -- CST continuous simulated tempering -- PCA principal component analysis -- ADT androgen deprivation therapy -- IAD intermittent androgen deprivation -- BAT bipolar androgen treatment; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.05.011
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: 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. Graphical Abstract: Unlabelled Image Highlights: PAGE4 is a disordered protein that changes size upon different levels of phosphorylation. We introduced a novel MD-based model for simulating IDP conformational dynamics. MD simulations reproduce experimental data, uncover underlying molecular mechanism. PAGE4 conformational dynamics may affect phenotypic plasticity in PCa. Elucidates conformational switching dynamics for PAGE4 and its implications in PCa.