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  • Downsizing Proto-oncogene cFos to Short Helix-Constrained Peptides that Bind Jun

    Author(s)
    Baxter, Daniel
    Perry, Samuel R.
    Hill, Timothy A.
    Kok, W. Mei
    Zaccai, Nathan R.
    Brady, R. Leo
    Fairlie, David P.
    Mason, Jody M.
    Griffith University Author(s)
    Perry, Samuel
    Year published
    2017
    Metadata
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    Abstract
    The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37–25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos-derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble α-helices ...
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    The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37–25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos-derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble α-helices by connecting amino acid side chains to form cyclic pentapeptide components. Structural integrity in the presence and absence of Jun was assessed by circular dichroism spectroscopy, while the thermodynamics of binding to cFos was measured by isothermal titration calorimetry. A 25-residue constrained peptide, one-third shorter yet 25% more helical than the structurally characterized 37-residue Fos-derived peptide, retained 80% of the binding free energy as a result of preorganization in a Jun-binding helix conformation, with the entropy gain (TΔS = +3.2 kcal/mol) compensating for the enthalpy loss. Attaching a cell-penetrating peptide (TAT48–57) and a nuclear localization signal (SV40) promoted cell uptake, localization to the nucleus, and inhibition of the proliferation of two breast cancer cell lines.
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    Journal Title
    ACS Chemical Biology
    Volume
    12
    Issue
    8
    DOI
    https://doi.org/10.1021/acschembio.7b00303
    Subject
    Medicinal and Biomolecular Chemistry not elsewhere classified
    Chemical Sciences
    Biological Sciences
    Publication URI
    http://hdl.handle.net/10072/370485
    Collection
    • Journal articles

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