title: Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells.
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.
authors.affiliation: 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.
authors.forename: Wade
authors.initials: W
authors.lastname: Borcherds
authors.affiliation: In-cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Theillet
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Katzer
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Finzel
authors.affiliation: 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.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Mishall
authors.affiliation: 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.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Powell
authors.affiliation: 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.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Drug Discovery Department, Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Manieri
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: In-cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Selenko
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Loewer
authors.affiliation: 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.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Daughdrill
mesh_terms: D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D064267:Intrinsically Disordered Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2