To assess the potential of mutations from the L1 loop of the tumour suppressor p53 as second-site suppressors, the effect of H115N and S116M on the p53 ‘hot spot’ mutations has been investigated using the double-mutant approach. The effects of these two mutants on the p53 hot spots in terms of thermal stability and DNA binding were evaluated. The results show that: (i) the p53 mutants H115N and S116M are thermally more stable than wild-type p53; (ii) H115N but not S116M is capable of rescuing the DNA binding of one of the most frequent p53 mutants in cancer, R248Q, as shown by binding of R248Q/H115N to gadd45 (the promoter of a gene involved in cell-cycle arrest); (iii) the double mutant R248Q/H115N is more stable than wild-type p53; (iv) the effect of H115N as a second-site suppressor to restore DNA-binding activity is specific to R248Q, but not to R248W; (v) molecular-dynamics simulations indicate that R248Q/H115N has a conformation similar to wild-type p53, which is distinct from that of R248Q. These findings could be exploited in designing strategies for cancer therapy to identify molecules that could mimic the effect of H115N in restoring function to oncogenic p53 mutants.
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Research Article|
March 29 2010
Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights
Assia Merabet;
Assia Merabet
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Hellen Houlleberghs;
Hellen Houlleberghs
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Kate Maclagan;
Kate Maclagan
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Ester Akanho;
Ester Akanho
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Tam T. T. Bui;
Tam T. T. Bui
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Bruno Pagano;
Bruno Pagano
†Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, London, SE1 1UL, U.K.
‡Dipartimento di Scienze Farmaceutiche, Universita di Salerno, via Ponte Don Melillo, Fisciano (SA) I-84084, Italy
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Alex F. Drake;
Alex F. Drake
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
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Franca Fraternali;
Franca Fraternali
†Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, London, SE1 1UL, U.K.
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Penka V. Nikolova
Penka V. Nikolova
1
*Department of Biochemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, U.K.
1To whom correspondence should be addressed (email penka.nikolova@kcl.ac.uk).
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Publisher: Portland Press Ltd
Received:
December 14 2009
Revision Received:
January 25 2010
Accepted:
January 29 2010
Accepted Manuscript online:
January 29 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 427 (2): 225–236.
Article history
Received:
December 14 2009
Revision Received:
January 25 2010
Accepted:
January 29 2010
Accepted Manuscript online:
January 29 2010
Citation
Assia Merabet, Hellen Houlleberghs, Kate Maclagan, Ester Akanho, Tam T. T. Bui, Bruno Pagano, Alex F. Drake, Franca Fraternali, Penka V. Nikolova; Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights. Biochem J 15 April 2010; 427 (2): 225–236. doi: https://doi.org/10.1042/BJ20091888
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