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The novel p53 isoform “delta p53” is a misfolded protein and does not bind the p21 promoter site
Author(s) -
GarcíaAlai Maria M.,
Tidow Henning,
Natan Eviatar,
Townsley Fiona M.,
Veprintsev Dmitry B.,
Fersht Alan R.
Publication year - 2008
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.036996.108
Subject(s) - gene isoform , alternative splicing , exon , rna splicing , linker , biology , gene , microbiology and biotechnology , chemistry , genetics , rna , computer science , operating system
The tumor suppressor p53 can be expressed as different isoforms because of promoter selection and mRNA editing. One isoform, “delta p53” (Δp53), 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 Δp53 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 Δp53 and flp53 is soluble in vitro and binds poorly to DNA. Our results provide a structural explanation for the dominant‐negative effect of Δp53 and its lack of transcriptional activity.