例如:"lncRNA", "apoptosis", "WRKY"

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity.

Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2644-E2653. Epub 2017 Mar 13
Prakash Kulkarni 1 , Mohit Kumar Jolly 2 , Dongya Jia 3 , Steven M Mooney 4 , Ajay Bhargava 5 , Luciane T Kagohara 6 , Yihong Chen 7 , Pengyu Hao 8 , Yanan He 7 , Robert W Veltri 6 , Alexander Grishaev 7 , Keith Weninger 8 , Herbert Levine 9 , John Orban 10
Prakash Kulkarni 1 , Mohit Kumar Jolly 2 , Dongya Jia 3 , Steven M Mooney 4 , Ajay Bhargava 5 , Luciane T Kagohara 6 , Yihong Chen 7 , Pengyu Hao 8 , Yanan He 7 , Robert W Veltri 6 , Alexander Grishaev 7 , Keith Weninger 8 , Herbert Levine 9 , John Orban 10
+ et al

[No authors listed]

Author information
  • 1 Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; herbert.levine@rice.edu pkulkar4@ibbr.umd.edu jorban@umd.edu.
  • 2 Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
  • 3 Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005.
  • 4 Department of Biology, University of Waterloo, Waterloo, ON Canada N2L 3G1.
  • 5 Shakti BioResearch, Woodbridge, CT 06525.
  • 6 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 7 Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850.
  • 8 Department of Physics, North Carolina State University, Raleigh, NC 27695.
  • 9 Department of Bioengineering, Rice University, Houston, TX 77005.
  • 10 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742.

摘要


Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgen-dependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgen-dependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.

KEYWORDS: PAGE-4, androgen resistance, intrinsic disorder, phenotypic heterogeneity, prostate cancer