PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer

Lin, Xingcheng and Roy, Susmita and Jolly, Mohit Kumar and Bocci, Federico and Schafer, Nicholas P and Tsai, Min-Yeh and Chen, Yihong and He, Yanan and Grishaev, Alexander and Weninger, Keith and Orban, John and Kulkarni, Prakash and Rangarajan, Govindan and Levine, Herbert and Onuchic, Jose N (2018) PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer. In: JOURNAL OF MOLECULAR BIOLOGY, 430 (16, SI). pp. 2422-2438.

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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. SmallangleX-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 of different 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. (C) 2018 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Publication:	JOURNAL OF MOLECULAR BIOLOGY
Publisher:	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
Additional Information:	Copyright of this article belong to ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
Department/Centre:	Division of Physical & Mathematical Sciences > Mathematics
Date Deposited:	08 Aug 2018 15:45
Last Modified:	08 Aug 2018 15:45
URI:	http://eprints.iisc.ac.in/id/eprint/60360

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