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Biomolecules. 2019 Feb 22;9(2). pii: E77. doi: 10.3390/biom9020077.

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level.

Lin X1,2,3, Kulkarni P4, Bocci F5,6, Schafer NP7,8, Roy S9, Tsai MY10,11,12, He Y13, Chen Y14, Rajagopalan K15, Mooney SM16, Zeng Y17, Weninger K18, Grishaev A19,20, Onuchic JN21,22,23,24, Levine H25,26, Wolynes PG27,28, Salgia R29, Rangarajan G30,31, Uversky V32,33, Orban J34,35, Jolly MK36,37.

Author information

1
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. xclin@mit.edu.
2
Department of Physics and Astronomy, Rice University, Houston, TX 77005, USA. xclin@mit.edu.
3
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. xclin@mit.edu.
4
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. pkulkarni@coh.org.
5
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. fb20@rice.edu.
6
Department of Chemistry, Rice University, Houston, TX 77005, USA. fb20@rice.edu.
7
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. npschafer@gmail.com.
8
Department of Chemistry, Rice University, Houston, TX 77005, USA. npschafer@gmail.com.
9
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. susmitajanaroy@gmail.com.
10
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. mytsai886@gmail.com.
11
Department of Chemistry, Rice University, Houston, TX 77005, USA. mytsai886@gmail.com.
12
Department of Chemistry, Tamkang University, New Taipei City 25137, Taiwan. mytsai886@gmail.com.
13
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA. hey@umd.edu.
14
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA. yihong@umd.edu.
15
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. krrajagopalan@ucsd.edu.
16
Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada. steve.mooney@uwaterloo.ca.
17
Department of Urology, The First Hospital of China Medical University Shenyang, Shenyang 110001, China. zengyud@hotmail.com.
18
Department of Physics, North Carolina State University, Raleigh, NC 27695, USA. krwening@ncsu.edu.
19
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA. agrishaev@ibbr.umd.edu.
20
National Institute of Standards and Technology, Gaithersburg, MD 20899, USA. agrishaev@ibbr.umd.edu.
21
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. jonuchic@rice.edu.
22
Department of Physics and Astronomy, Rice University, Houston, TX 77005, USA. jonuchic@rice.edu.
23
Department of Chemistry, Rice University, Houston, TX 77005, USA. jonuchic@rice.edu.
24
Department of BioSciences, Rice University, Houston, TX 77005, USA. jonuchic@rice.edu.
25
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. herbert.levine@rice.edu.
26
Department of Physics, Northeastern University, Boston, MA 02115, USA. herbert.levine@rice.edu.
27
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. pwolynes@rice.edu.
28
Department of Chemistry, Rice University, Houston, TX 77005, USA. pwolynes@rice.edu.
29
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. rsalgia@coh.org.
30
Department of Mathematics, Indian Institute of Science, Bangalore 560012, India. rangaraj@iisc.ac.in.
31
Center for Neuroscience, Indian Institute of Science, Bangalore 560012, India. rangaraj@iisc.ac.in.
32
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. vuversky@health.usf.edu.
33
Laboratory of New methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia. vuversky@health.usf.edu.
34
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA. jorban@umd.edu.
35
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. jorban@umd.edu.
36
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA. mkjolly@iisc.ac.in.
37
Center for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India. mkjolly@iisc.ac.in.

Abstract

Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.

KEYWORDS:

PAGE4; conformational plasticity; intrinsically disordered proteins; order–disorder transition; phosphorylation

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