Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36.
Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36.
复制标题
DOI：
10.1038/s41586-018-0209-9
复制
发表时间：
2018-06
期刊：
影响因子：
64.8
通讯作者：
Ferré-D'Amaré AR
中科院分区：
文献类型：
--
作者：
Chen MC;Tippana R;Demeshkina NA;Murat P;Balasubramanian S;Myong S;Ferré-D'Amaré AR
富含鸟嘌呤的核酸序列通过自发地折叠成G-四链来挑战复制、转录和翻译机制，而G-四链的展开需要比大多数聚合酶所能施加的更大的力。真核细胞拥有许多能够解开G-四链体的解旋酶。解旋酶识别和打开G-四链的分子基础仍然知之甚少。DHX36(RHAU，G4R1)是Deah/RHA解旋酶家族的成员，以独特的高亲和力结合DNA和RNA G-四链体，一直被发现与细胞中的G-四链体结合，是HeLa细胞裂解产物G-四链体解折叠活性的主要来源。DHX36是一种多功能解旋酶，参与G-四链介导的转录和转录后调控，对小鼠心脏发育、造血和胚胎发育至关重要。在这里，我们报道了牛DHX36与带有G-四链和3‘-单链(SsDNA)片段的DNA结合的共晶结构。我们发现，DHX36的N端基序折叠成一个DNA结合诱导的α螺旋，它与OB折叠样亚结构域一起选择性地结合平行的G-四链。与我们的未连接和ATP类似物结合的DHX36结构的比较，以及单分子FRET分析，表明G-四链结合单独引起解旋酶核心的重排，通过拉动其单链DNA尾巴，驱动G-四链一次一个残基的展开。
Guanine-rich nucleic acid sequences challenge the replication, transcription, and translation machinery by spontaneously folding into G-quadruplexes, the unfolding of which requires forces greater than what most polymerases can exert. Eukaryotic cells host numerous helicases capable of unfolding G-quadruplexes. The molecular basis for helicase recognition and unfolding of G-quadruplexes remains poorly understood. DHX36 (RHAU, G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with uniquely high affinity, is consistently found bound to G-quadruplexes in cells, and is a major source of G-quadruplex unfolding activity in HeLa cell lysates. DHX36 is a multi-functional helicase implicated in G-quadruplex-mediated transcriptional and post-transcriptional regulation, and is essential for heart development, hematopoiesis, and embryogenesis in mice. Here, we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3’ single-stranded (ssDNA) segment. We show that the N-terminal DHX36-specific motif folds into a DNA-binding-induced α-helix that together with the OB-fold-like subdomain selectively binds parallel G-quadruplexes. Comparison with our unliganded and ATP-analog-bound DHX36 structures, together with single-molecule FRET analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core, which by pulling on its ssDNA tail, drive G-quadruplex unfolding by one residue at a time.
登录
查看更多内容
影响因子：
14.9
作者：
Lattmann S;Giri B;Vaughn JP;Akman SA;Nagamine Y
通讯作者：
Nagamine Y
DOI：
10.1073/pnas.1422605112
发表时间：
2015-08-04
影响因子：
11.1
作者：
Heddi, Brahim;Cheong, Vee Vee;Anh Tuan Phan
通讯作者：
Anh Tuan Phan
DOI：
10.1107/s0907444903018043
发表时间：
2003-11-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Grosse-Kunstleve, RW;Adams, PD
通讯作者：
Adams, PD
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.7
作者：
He, Yangzi;Andersen, Gregers R.;Nielsen, Klaus H.
通讯作者：
Nielsen, Klaus H.