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THE NOVEL p53 ISOFORM "DELTA p53" IS A MISFOLDED PROTEIN AND DOES NOT BIND THE p21 PROMOTER SITE

¹ CPE;
² Cambridge

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

The tumor suppressor p53 can be expressed as different isoforms as a consequence of promoter selection and mRNA editing. One isoform, "delta p53" (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 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 co-expressed p53 and flp53 is soluble in vitro and binds poorly to DNA. Our results provide a structural explanation for the dominant-negative effect of p53 and the lack of transcriptional activity.

Keywords: Protein Structure/Folding; Structure/function studies; DNA-binding Domains:; Mass Spectrometry; Correlation of structure with spectra and other properties; Other Spectroscopies; Circular dichroism; Fluorescence; Thermodynamics, Hydrodynamics; SAXS

³ E-mail: arf25{at}cam.ac.uk

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