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Imaging and kinetics of the bimolecular complex formed by the tumor suppressor p53 with ubiquitin ligase COP1 as studied by atomic force microscopy and surface plasmon resonance

Authors Moscetti I, Bizzarri AR, Cannistraro S

Received 21 September 2017

Accepted for publication 28 November 2017

Published 4 January 2018 Volume 2018:13 Pages 251—259

DOI https://doi.org/10.2147/IJN.S152214

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Govarthanan Muthusamy

Peer reviewer comments 3

Editor who approved publication: Dr Thomas Webster


Ilaria Moscetti, Anna Rita Bizzarri, Salvatore Cannistraro

Biophysics and Nanoscience Centre, Department of Ecology and Biology, Università della Tuscia, Viterbo, Italy

Abstract: p53 plays an important role in the safeguard of the genome but it is frequently downregulated mainly by E3 ubiquitin ligases among which COP1 plays an important role. The overexpression of COP1 has been reported to occur in several tumors and may be indicative of its overall oncogenic effect, which in turn might be originated by a direct interaction of COP1 with p53. Such an interaction may constitute a rewarding target for anticancer drug design strategies; therefore, a deeper understanding of its underlying molecular mechanism and kinetics is needed. The formation of a single p53–COP1 bimolecular complex was visualized by atomic force microscopy imaging on a mica substrate. The kinetic characterization of the complex, performed by atomic force spectroscopy and surface plasmon resonance, provided a KD value of ~10-8 M and a relative long lifetime in the order of minutes, both at the single-molecule level and in bulk solution. The surprisingly high affinity value and low dissociation rate of the p53–COP1 bimolecular complex, which is even stronger than the p53–MDM2 complex, should be considered a benchmark for designing, development and optimization of suitable drugs able to antagonize the complex formation with the aim of preventing the inhibitory effect of COP1 on the p53 oncosuppressive function.

Keywords: p53, COP1, AFM, AFS, SPR, protein–protein interaction
 

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