Intrinsic disorder and coiled-coil formation in prostate apoptosis response factor 4

David S. Libich, Martin Schwalbe, Sachin Kate, Hariprasad Venugopal, Jolyon K. Claridge, Patrick J.B. Edwards, Kaushik Dutta, Steven M. Pascal

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Prostate apoptosis response factor-4 (Par-4) is an ubiquitously expressed pro-apoptotic and tumour suppressive protein that can both activate cell-death mechanisms and inhibit pro-survival factors. Par-4 contains a highly conserved coiled-coil region that serves as the primary recognition domain for a large number of binding partners. Par-4 is also tightly regulated by the aforementioned binding partners and by post-translational modifications. Biophysical data obtained in the present study indicate that Par-4 primarily comprises an intrinsically disordered protein. Bioinformatic analysis of the highly conserved Par-4 reveals low sequence complexity and enrichment in polar and charged amino acids. The high proteolytic susceptibility and an increased hydrodynamic radius are consistent with a largely extended structure in solution. Spectroscopic measurements using CD and NMR also reveal characteristic features of intrinsic disorder. Under physiological conditions, the data obtained show that Par-4 self-associates via the C-terminal domain, forming a coiled-coil. Interruption of self-association by urea also resulted in loss of secondary structure. These results are consistent with the stabilization of the coiled-coil motif through an intramolecular association.

Original languageEnglish (US)
Pages (from-to)3710-3728
Number of pages19
JournalFEBS Journal
Volume276
Issue number14
DOIs
StatePublished - Jul 2009
Externally publishedYes

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Keywords

  • Circular dichroism
  • Coiled-coil
  • Intrinsically disordered protein
  • Prostate apoptosis response factor 4
  • Solution NMR spectroscopy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Libich, D. S., Schwalbe, M., Kate, S., Venugopal, H., Claridge, J. K., Edwards, P. J. B., Dutta, K., & Pascal, S. M. (2009). Intrinsic disorder and coiled-coil formation in prostate apoptosis response factor 4. FEBS Journal, 276(14), 3710-3728. https://doi.org/10.1111/j.1742-4658.2009.07087.x