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

Wade Borcherds; François-Xavier Theillet; Andrea Katzer; Ana Finzel; Katie M Mishall; Anne T Powell; Hongwei Wu; Wanda Manieri; Christoph Dieterich; Philipp Selenko; Alexander Loewer; Gary W Daughdrill

doi:10.1038/nchembio.1668

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

Nat Chem Biol. 2014 Dec;10(12):1000-2. doi: 10.1038/nchembio.1668. Epub 2014 Nov 2.

Affiliations

¹ 1] Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA. [2] Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida, USA.
² In-cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany.
³ Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
⁴ Drug Discovery Department, Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA.
⁵ Max Planck Institute for Biology of Ageing, Cologne, Germany.

PMID: 25362358
DOI: 10.1038/nchembio.1668

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Cycle / genetics
Cell Cycle / radiation effects
Cell Line, Tumor
DNA Damage
Escherichia coli / genetics
Escherichia coli / metabolism
Gamma Rays
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
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

Substances

Intrinsically Disordered Proteins
Recombinant Proteins
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2