Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence.
Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence.
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DOI：
10.1093/nar/gkab302
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发表时间：
2021-06-04
影响因子：
14.9
通讯作者：
Zhu G
中科院分区：
文献类型：
--
作者：
Geng Y;Liu C;Cai Q;Luo Z;Miao H;Shi X;Xu N;Fung CP;Choy TT;Yan B;Li N;Qian P;Zhou B;Zhu G
已知C9orf72基因第一个内含子内的六核苷酸重复扩增GGGGCC （G4C2）是肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。G4C2重复扩增，无论是DNA还是RNA，都能够形成g -四联体，诱导毒性导致ALS/FTD。本文报道了一种新的d(G4C2)2晶体结构，它可以自结合形成八层平行四聚体g -四聚体。两个d(G4C2)2结合成平行的二聚体g -四聚体，通过5′到5′排列折叠成四聚体。每个二聚体由四个g四聚体组成，由两个CC螺旋桨环连接。特别是3′端胞嘧啶突出，在二聚体上形成C·C+•C·C+/ C·C·C·C+四碱基对或C·C·C+三碱基对堆叠。我们的工作揭示了d（G4C2）采用的g -四联体，并为开发治疗神经退行性疾病，ALS和FTD的小分子提供了宝贵的结构细节。
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.
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DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
14.9
作者：
Brcic J;Plavec J
通讯作者：
Plavec J
影响因子：
3.5
作者：
Miyoshi, D;Nakao, A;Sugimoto, N
通讯作者：
Sugimoto, N
G-四链体折叠和稳定性中的金属阳离子。
影响因子：
5.5
作者：
Bhattacharyya D;Mirihana Arachchilage G;Basu S
通讯作者：
Basu S