title: The Lys-Specific Molecular Tweezer, CLR01, Modulates Aggregation of the Mutant p53 DNA Binding Domain and Inhibits Its Toxicity.
abstract: The tumor suppressor p53 plays a unique role as a central hub of numerous cell proliferation and apoptotic pathways, and its malfunction due to mutations is a major cause of various malignancies. Therefore, it serves as an attractive target for developing novel anticancer therapeutics. Because of its intrinsically unstable DNA binding domain, p53 unfolds rapidly at physiological temperature. Certain mutants shift the equilibrium toward the unfolded state and yield high-molecular weight, nonfunctional, and cytotoxic β-sheet-rich aggregates that share tinctorial and conformational similarities with amyloid deposits found in various protein misfolding diseases. Here, we examined the effect of a novel protein assembly modulator, the lysine (Lys)-specific molecular tweezer, CLR01, on different aggregation stages of misfolded mutant p53 in vitro and on the cytotoxicity of the resulting p53 aggregates in cell culture. We found that CLR01 induced rapid formation of β-sheet-rich, intermediate-size p53 aggregates yet inhibited further p53 aggregation and reduced the cytotoxicity of the resulting aggregates. Our data suggest that aggregation modulators, such as CLR01, could prevent the formation of toxic p53 aggregates.
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Gal
authors.initials: G
authors.lastname: Herzog
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Merav D
authors.initials: MD
authors.lastname: Shmueli
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Limor
authors.initials: L
authors.lastname: Levy
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Liat
authors.initials: L
authors.lastname: Engel
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
authors.affiliation: ‡Institute of Organic Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
authors.forename: Frank-Gerrit
authors.initials: FG
authors.lastname: Klärner
authors.affiliation: ‡Institute of Organic Chemistry, University of Duisburg-Essen, 45117 Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
authors.affiliation: §Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095-7334, United States.
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.affiliation: †Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978.
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D058767:Protein Unfolding / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D010755:Organophosphates; D066329:Protein Aggregates; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53