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pH-induced folding of an apoptotic coiled coil

Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York 14642, USA

Reprint requests to: Kaushik Dutta and Steven M. Pascal, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Box 712, 601 Elmwood Avenue, Rochester, NY 14642; e-mail: kaushik_dutta{at}urmc.rochester.edu; pascal{at}oxbow.biophysics.rochester.edu; fax: (716) 275-6007.

Par-4 is a 38-kD protein pivotal to the apoptotic pathways of various cell types, most notably prostate cells and neurons, where it has been linked to prostate cancer and various neurodegenerative disorders including Alzheimer's and Huntington's diseases and HIV encephalitis. The C-terminal region of Par-4 is responsible for homodimerization and the ability of Par-4 to interact with proposed effector molecules. In this study, we show that the C-terminal 47 residues of Par-4 are natively unfolded at physiological pH and temperature. Evidence is rapidly accumulating that natively unfolded proteins play an important role in various cellular functions and signaling pathways, and that folding can often be induced on complexation with effector molecules or alteration of environment. Here we use primarily CD studies to show that changes in the environment, particularly pH and temperature, can induce the Par-4 C terminus to form a self-associated coiled coil.

Keywords: Leucine zipper; coiled coil; apoptosis; circular dichroism; protein folding; natively unfolded

Abbreviations: Par-4, prostate apoptosis response protein number 4 • LZ, leucine zipper • PKC, protein kinase C • aPKC, atypical protein kinase C • MBP, maltose-binding protein • CD, circular dichroism • [], molar ellipticity • [222], molar ellipticity at 222 nm • [D], molar ellipticity at 222 nm at the low pH limit • [M], molar ellipticity at 222 nm at the high pH limit • n, Hill coefficient • Tm, characteristic melting temperature • fM, fractional population of monomer state • Kd, dissociation constant • Ctot, total concentration of peptide • Hm, enthalpy of melting • Cp, change in heat capacity at constant pressure • [D0], molar ellipticity at 222 nm at the low pH limit extrapolated to 0 K • , constant describing the slope of [D] versus temperature • [208], molar ellipticity at 208 nm • WT1, Wilm's tumor protein • Dlk, DAP-like kinase.

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