The novel p53 isoform "delta p53" is a misfolded protein and does not bind the p21 promoter site.
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 beta10 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.
García-Alai
Maria M
MM
Medical Research Council Centre for Protein Engineering, Cambridge CB2 0QH, United Kingdom.
Tidow
Henning
H
Natan
Eviatar
E
Townsley
Fiona M
FM
Veprintsev
Dmitry B
DB
Fersht
Alan R
AR
D017398:Alternative Splicing; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53