In the past year, we have made progress in the subject of selective cation binding by RNA and how this can regulate gene expression. Through a combination of biophysical, biochemical and crystallographic analyses, we have determined how a bacterial gene-regulatory RNA (riboswitch), which was shown to bind to Mn(II) by our collaborators in the Storz laboratory at NICHD can also bind with high affinity to Cd(II) and control gene expression. We discovered that this RNA exploits the unusual ability of these two ions to adopt a heptacoordinated geometry to distinguish them from the majority of other metal ions (that are typically hexacoordinated). This insight could drive the design of biosensors, as well as potential detoxyfying agents. In collaboration with the Balasubramanian and Myong laboratories (Cambridge University and Johns Hopkins University, respectively) we have also made an important advance in understanding the molecular mechanism of the DEAH family of helicases, widespread and essential proteins that remodel cellular RNAs and RNPs. Our structural and single-molecule characterization of DHX36, an essential helicase involved in control of gene expression, the stress response, and cardiovascular development, revealed how these enzymes can use the energy of binding to the nucleic acid substrate alone to perform mechanical work. DHX36 is notable for its high specificity for G-quadruplex containing nucleic acids, and our structural analysis is also the first to show how the cellular machinery can recognize and remodel this important type of DNA and RNA structures.

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Project End
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Budget End
Support Year
8
Fiscal Year
2018
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Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
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Chen, Michael C; Tippana, Ramreddy; Demeshkina, Natalia A et al. (2018) Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36. Nature 558:465-469
Lau, Matthew W L; Trachman 3rd, Robert J; Ferré-D'Amaré, Adrian R (2017) A divalent cation-dependent variant of the glmS ribozyme with stringent Ca(2+) selectivity co-opts a preexisting nonspecific metal ion-binding site. RNA 23:355-364
Miao, Zhichao; Adamiak, Ryszard W; Antczak, Maciej et al. (2017) RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme. RNA 23:655-672
Lau, Matthew W L; Ferré-D'Amaré, Adrian R (2016) In vitro evolution of coenzyme-independent variants from the glmS ribozyme structural scaffold. Methods 106:76-81
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Zhang, Jinwei; Ferré-DAmaré, Adrian R (2016) Trying on tRNA for Size: RNase P and the T-box Riboswitch as Molecular Rulers. Biomolecules 6:
Zhang, Jinwei; Ferré-D'Amaré, Adrian R (2016) The tRNA Elbow in Structure, Recognition and Evolution. Life (Basel) 6:
Miao, Zhichao; Adamiak, Ryszard W; Blanchet, Marc-Frédérick et al. (2015) RNA-Puzzles Round II: assessment of RNA structure prediction programs applied to three large RNA structures. RNA 21:1066-84
Zhang, Jinwei; Ferré-D'Amaré, Adrian R (2015) Structure and mechanism of the T-box riboswitches. Wiley Interdiscip Rev RNA 6:419-33
Ferré-D'Amaré, Adrian R (2015) On the shoulders of giants. RNA 21:504-5

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