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Published online before print July 15, 2008, 10.1110/ps.036996.108
Protein Science (2008), 17:1671-1678. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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The novel p53 isoform "delta p53" is a misfolded protein and does not bind the p21 promoter site

Maria M. García-Alai, Henning Tidow, Eviatar Natan, Fiona M. Townsley, Dmitry B. Veprintsev, and Alan R. Fersht

Medical Research Council Centre for Protein Engineering, Cambridge CB2 0QH, United Kingdom

(RECEIVED June 12, 2008; FINAL REVISION July 4, 2008; ACCEPTED July 4, 2008)

The tumor suppressor p53 can be expressed as different isoforms because of promoter selection and mRNA editing. One isoform, "delta p53" ({Delta}p53), results from what would be an unusual alternative splicing of exons 7/8 of the p53 gene, conserving the reading frame and generating a novel protein with proposed transcriptional activity essential for the intra S-phase checkpoint. Here, we show that the deletion of the 66 residues that correspond to strand β10 and the C-terminal helix of the core domain and the interconnecting linker to the tetramerization domain occurring in the {Delta}p53 isoform leads to a misfolded and unstable protein, prone to form soluble aggregates, which does not bind the p21 promoter site. The complex of coexpressed {Delta}p53 and flp53 is soluble in vitro and binds poorly to DNA. Our results provide a structural explanation for the dominant-negative effect of {Delta}p53 and its lack of transcriptional activity.

Keywords: protein structure/folding; structure/function studies; DNA-binding domains; dominant-negative mutation


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