The Hairpin Form of r(G
| Autor: | Zi-Fu, Wang, Andrei, Ursu, Jessica L, Childs-Disney, Rea, Guertler, Wang-Yong, Yang, Viachaslau, Bernat, Suzanne G, Rzuczek, Rita, Fuerst, Yong-Jie, Zhang, Tania F, Gendron, Ilyas, Yildirim, Brendan G, Dwyer, Joseph E, Rice, Leonard, Petrucelli, Matthew D, Disney |
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| Rok vydání: | 2018 |
| Předmět: |
Binding Sites
DNA Repeat Expansion C9orf72 Protein Amyotrophic Lateral Sclerosis RNA-Binding Proteins Molecular Dynamics Simulation Article Small Molecule Libraries Kinetics Frontotemporal Dementia Polyribosomes Protein Biosynthesis Humans Nucleic Acid Conformation Thermodynamics Nuclear Magnetic Resonance Biomolecular |
| Zdroj: | Cell chemical biology. 26(2) |
| ISSN: | 2451-9448 |
| Popis: | The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G(4)C(2) repeat [(G(4)C(2))(exp)] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(G(4)C(2))(exp)], which sequesters RNA-binding proteins (RBPs) and undergoes repeat associated non-ATG (RAN) translation to generate toxic dipeptide repeats. Using in vitro and cell-based assays, we identified a small molecule (4) that selectively bound r(G(4)C(2))(exp), prevented sequestration of an RBP, and inhibited RAN translation. Indeed, biophysical characterization showed that 4 selectively bound the hairpin form of r(G(4)C(2))(exp), and NMR spectroscopy studies and molecular dynamics simulations defined this molecular recognition event. Cellular imaging revealed that 4 localized to r(G(4)C(2))(exp) cytoplasmic foci, the putative sites of RAN translation. Collectively, these studies highlight that the hairpin structure of r(G(4)C(2))(exp) is a therapeutically relevant target and small molecules that bind it can ameliorate c9ALS/FTD-associated toxicity. |
| Databáze: | OpenAIRE |
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