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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 modifica-tions. | Intrinsic disorder and coiled-coil formation in prostate apoptosis response factor 4 David S. Libich1 Martin Schwalbe1 Sachin Kate1 Hariprasad Venugopal1 Jolyon K. Claridge1 Patrick J. B. Edwards1 Kaushik Dutta2 and Steven M. Pascal1 1 Centre for StructuralBiology Institute of Fundamental sciences and Department of Physics Massey University Palmerston North New Zealand 2 New York StructuralBiology Centre NY USA Keywords circular dichroism coiled-coil intrinsically disordered protein prostate apoptosis response factor 4 solution NMR spectroscopy Correspondence D. S. Libich or S. M. Pascal Institute of FundamentalSciences Massey University Turitea Site Private Bag 11222 Palmerston North 4442 New Zealand Fax 64 6 350 5682 Tel 64 6 356 9099 E-mails d.s.libich@massey.ac.nz s.pascal@massey.ac.nz These authors contributed equally to this work Received 24 March 2009 accepted 6 May 2009 Prostate apoptosis response factor-4 Par-4 is an ubiquitously expressed pro-apoptotic and tumour suppressive protein that can both activate celldeath 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
