Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells

• Published in: Nature chemical biology Vol. 10; no. 12; pp. 1000 - 1002
• Main Authors: Borcherds, Wade, Theillet, François-Xavier, Katzer, Andrea, Finzel, Ana, Mishall, Katie M, Powell, Anne T, Wu, Hongwei, Manieri, Wanda, Dieterich, Christoph, Selenko, Philipp, Loewer, Alexander, Daughdrill, Gary W
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2014; Nature Publishing Group
• Subjects: 101/6; 13; 13/95; 14; 14/63; 38; 38/39; 38/91; 631/45; 631/535/878; 631/67; 631/80/86; 96/35; Binding sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; brief-communication; Cell Biology; Cell cycle; Cell Cycle - genetics; Cell Cycle - radiation effects; Cell Line, Tumor; Chemistry; Chemistry/Food Science; Deoxyribonucleic acid; DNA; DNA Damage; Escherichia coli - genetics; Escherichia coli - metabolism; Gamma Rays; Gene expression; Gene Expression Regulation; Humans; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Models, Molecular; Mutation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Proto-Oncogene Proteins c-mdm2 - chemistry; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1668

Increasing residual helicity in the p53 transcriptional activation domain strengthened interactions with Mdm2, resulting in alterations in p53 protein dynamics, impaired transcription of target genes and failure to promote cell cycle arrest. Levels of residual structure in disordered interaction domains determine in vitro binding affinities, but whether they exert similar roles in cells is not known. Here, we show that increasing residual p53 helicity results in stronger Mdm2 binding, altered p53 dynamics, impaired target gene expression and failure to induce cell cycle arrest upon DNA damage. These results establish that residual structure is an important determinant of signaling fidelity in cells.