Downsizing proto-oncogene cFos to short helix-constrained peptides that bind Jun

Baxter, Daniel, Perry, Samuel R., Hill, Timothy A., Kok, W. Mei, Zaccai, Nathan R., Brady, R. Leo, Fairlie, David P. and Mason, Jody M. (2017) Downsizing proto-oncogene cFos to short helix-constrained peptides that bind Jun. ACS Chemical Biology, 12 8: 2051-2061. doi:10.1021/acschembio.7b00303


Author Baxter, Daniel
Perry, Samuel R.
Hill, Timothy A.
Kok, W. Mei
Zaccai, Nathan R.
Brady, R. Leo
Fairlie, David P.
Mason, Jody M.
Title Downsizing proto-oncogene cFos to short helix-constrained peptides that bind Jun
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8937
1554-8929
Publication date 2017-08-18
Year available 2017
Sub-type Article (original research)
DOI 10.1021/acschembio.7b00303
Open Access Status Not yet assessed
Volume 12
Issue 8
Start page 2051
End page 2061
Total pages 11
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1303 Biochemistry
1313 Molecular Medicine
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 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 (TAT) and a nuclear localization signal (SV40) promoted cell uptake, localization to the nucleus, and inhibition of the proliferation of two breast cancer cell lines.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID A11738
BB/J011290/2
EP/M001873/2
1027369
DP160104442
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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