Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence
| Autor: | Naining Xu, Ning Li, To To Choy, Pei-Yuan Qian, Haitao Miao, Zhipu Luo, Guang Zhu, Xiao Shi, Bo Zhou, Qixu Cai, Changdong Liu, Chun Po Fung, Yanyan Geng, Bing Yan |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Protein Conformation AcademicSubjects/SCI00010 Base pair Stereochemistry Biology G-quadruplex Cytosine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein structure Tetramer Structural Biology Genetics Humans Repetitive Sequences Nucleic Acid 030304 developmental biology 0303 health sciences DNA Repeat Expansion C9orf72 Protein Circular Dichroism Amyotrophic Lateral Sclerosis Intron Hydrogen Bonding DNA G-Quadruplexes chemistry Frontotemporal Dementia Trinucleotide repeat expansion Dimerization 030217 neurology & neurosurgery |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkab302 |
| Popis: | The hexanucleotide repeat expansion, GGGGCC (G4C2), within the first intron of the C9orf72 gene is known to be the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 repeat expansions, either DNA or RNA, are able to form G-quadruplexes which induce toxicity leading to ALS/FTD. Herein, we report a novel crystal structure of d(G4C2)2 that self-associates to form an eight-layer parallel tetrameric G-quadruplex. Two d(G4C2)2 associate together as a parallel dimeric G-quadruplex which folds into a tetramer via 5′-to-5′ arrangements. Each dimer consists of four G-tetrads connected by two CC propeller loops. Especially, the 3′-end cytosines protrude out and form C·C+•C·C+/ C·C•C·C+ quadruple base pair or C•C·C+ triple base pair stacking on the dimeric block. Our work sheds light on the G-quadruplexes adopted by d(G4C2) and yields the invaluable structural details for the development of small molecules to tackle neurodegenerative diseases, ALS and FTD. |
| Databáze: | OpenAIRE |
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