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Nucleic Acids Research Advance Access published online on August 2, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn490
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax

Seema Patel1, Roger George2, Flavia Autore3, Franca Fraternali3, John E. Ladbury2 and Penka V. Nikolova1,*

1Department of Biochemistry and Pharmaceutical Science Division, School of Biomedical and Health Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford St., London SE1 9NH, 2Division of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT and 3Randall Division of Cell and Molecular Biophysics, New Hunt House, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK

*To whom correspondence should be addressed. Tel: +44 207 848 4276; Fax: +44 207 848 4500; Email: penka.nikolova{at}kcl.ac.uk

Received June 9, 2008. Revised July 15, 2008. Accepted July 16, 2008.

The apoptosis stimulating p53 proteins, ASPP1 and ASPP2, are the first two common activators of the p53 protein family that selectively enable the latter to regulate specific apoptotic target genes, which facilitates yes yet unknown mechanisms for discrimination between cell cycle arrest and apoptosis. To better understand the interplay between ASPP- and p53-family of proteins we investigated the molecular interactions between them using biochemical methods and structure-based homology modelling. The data demonstrate that: (i) the binding of ASPP1 and ASPP2 to p53, p63 and p73 is direct; (ii) the C-termini of ASPP1 and ASPP2 interact with the DNA-binding domains of p53 protein family with dissociation constants, Kd, in the lower micro-molar range; (iii) the stoichiometry of binding is 1:1; (iv) the DNA-binding domains of p53 family members are sufficient for these protein–protein interactions; (v) EMSA titrations revealed that while tri-complex formation between ASPPs, p53 family of proteins and PUMA/Bax is mutually exclusive, ASPP2 (but not ASPP1) formed a complex with PUMA (but not Bax) and displaced p53 and p73. The structure-based homology modelling revealed subtle differences between ASPP2 and ASPP1 and together with the experimental data provide novel mechanistic insights.


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