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Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36

机译：DEAH / RHA解旋酶DHX36解开G四联体的结构基础

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摘要

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 most polymerases can exert(1,2). Eukaryotic cells contain numerous helicases that can unfold G-quadruplexes(3). The molecular basis of the recognition and unfolding of G-quadruplexes by helicases remains poorly understood. DHX36 (also known as RHAU and G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with extremely high affinity(4-6), is consistently found bound to G-quadruplexes in and is a major source of G-quadruplex unfolding activity in HeLa cell lysates(6). DHX36 is a multi-functional helicase that has been implicated in G-quadruplex-mediated transcriptional and post transcriptional regulation, and is essential for heart development, haematopoiesis, and embryogenesis in mice(9-12). Here we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3' single-stranded DNA segment. We show that the N-terminal DHX36-specific motif folds into a DNA binding-induced alpha-helix that, together with the OB-fold-like subdomain, selectively binds parallel G-quadruplexes. Comparison with unliganded and ATP-analogue-bound DHX36 structures, together with single-molecule fluorescence resonance energy transfer (FRET) analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core; by pulling on the single-stranded DNA tail, these rearrangements drive G-quadruplex unfolding one residue at a time.
机译：富含鸟嘌呤的核酸序列通过自发折叠成G-四链体来挑战复制，转录和翻译机制，其展开需要比大多数聚合酶能施加的力更大的力（1,2）。真核细胞含有许多解旋酶，可以解开G-四链体（3）。对解旋酶识别和展开G-四链体的分子基础仍然知之甚少。 DHX36（也称为RHAU和G4R1）是DEAH / RHA解旋酶家族的成员，以极高的亲和力结合DNA和RNA G-四链体（4-6），始终被发现与G和C-四链体结合。 HeLa细胞裂解物中G-四链体展开活性的主要来源（6）。 DHX36是一种多功能解旋酶，已参与G-四链体介导的转录和转录后调控，对于小鼠的心脏发育，造血和胚胎发生必不可少（9-12）。在这里，我们报告牛DHX36的共晶体结构与具有G四联体和3'单链DNA片段的DNA结合。我们显示，N末端DHX36特异性基序折叠成DNA结合诱导的α-螺旋，与OB-fold-like子域一起，选择性结合平行的G-四链体。与未配体和ATP-类似物结合的DHX36结构进行比较，再加上单分子荧光共振能量转移（FRET）分析，表明单独的G-四链体结合会诱导解旋酶核心的重排。通过拉动单链DNA尾巴，这些重排驱动G-四链体一次解开一个残基。

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  • 来源
    《Nature》 |2018年第7710期|465-469|共5页
  • 作者

    Chen Michael C.; Tippana Ramreddy; Demeshkina Natalia A.; Murat Pierre; Balasubramanian Shankar; Myong Sua; Ferre-DAmare Adrian R.;

  • 作者单位

    NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA;

    Johns Hopkins Univ, Biophys Dept, Baltimore, MD USA;

    NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA;

    Univ Cambridge, Dept Chem, Cambridge, England;

    Univ Cambridge, Dept Chem, Cambridge, England;

    Johns Hopkins Univ, Biophys Dept, Baltimore, MD USA;

    NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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