RNAs that recognize small molecule ligands provide a widespread regulatory mechanism in biological systems. This study focuses on three RNAs that respond to small molecules, but in very different ways. Studies will be performed on the group I self-splicing RNA, the cooperative glycine riboswitch and a newly discovered riboswitch responsive to the second messenger cyclic diguanosine monophosphate (c-diGMP). 1. RNA splicing in response to the small molecule substrate guanosine. RNA splicing is the removal of an intron and the simultaneous ligation of its flanking exons in the generation of mature cellular RNA molecules. While most introns are removed by the spliceosome, some introns are able to catalyze their own removal from the primary transcript. The discovery of the group I class of introns provided the first indication that not all enzymes are proteins. Our goal is to structurally characterize each step in an RNA splicing pathway in order to understand how RNA functions as a catalyst. 2. Control of gene expression by cooperative binding of the amino acid glycine. Riboswitches are dynamic RNA folding domains that bind specific metabolites and control gene expression by modulation of transcription termination, translation initiation or RNA degradation. The glycine riboswitch comprises two similar aptamer domains that each bind glycine, but do so cooperatively. The result is a digital RNA sensor that is particularly sensitive to glycine concentration. Our goal is to understand the structural basis of glycine binding and cooperativity. 3. Analysis of a riboswitch responsive to a second messenger in the cell. c-dGMP was recently identified as a ligand for a broad collection of riboswitches, termed GEMM riboswitches. Our goal is to understand the structural and biochemical basis of c-diGMP binding by this new class of RNA molecule.
The importance of RNA splicing to human health is manifest by the observation that at least 15% of point mutations leading to heritable human diseases cause defects in pre-mRNA splicing. Riboswitches are prime candidates for antibiotic interventions toward the control of bacterial infections. The presence of the GEMM riboswitch in pathogenic organisms as well as the influence that the small molecule c-diGMP has on biofilm formation and virulence makes it a promising new drug target.
|Li, Sanshu; Breaker, Ronald R (2017) Identification of 15 candidate structured noncoding RNA motifs in fungi by comparative genomics. BMC Genomics 18:785|
|Nelson, James W; Atilho, Ruben M; Sherlock, Madeline E et al. (2017) Metabolism of Free Guanidine in Bacteria Is Regulated by a Widespread Riboswitch Class. Mol Cell 65:220-230|
|Reiss, Caroline W; Strobel, Scott A (2017) Structural basis for ligand binding to the guanidine-II riboswitch. RNA 23:1338-1343|
|Wang, Jimin; Moore, Peter B (2017) On the interpretation of electron microscopic maps of biological macromolecules. Protein Sci 26:122-129|
|Wang, Jimin; Askerka, Mikhail; Brudvig, Gary W et al. (2017) Insights into Photosystem II from Isomorphous Difference Fourier Maps of Femtosecond X-ray Diffraction Data and Quantum Mechanics/Molecular Mechanics Structural Models. ACS Energy Lett 2:397-407|
|Nelson, James W; Breaker, Ronald R (2017) The lost language of the RNA World. Sci Signal 10:|
|Lomakin, Ivan B; Stolboushkina, Elena A; Vaidya, Anand T et al. (2017) Crystal Structure of the Human Ribosome in Complex with DENR-MCT-1. Cell Rep 20:521-528|
|Wang, Jimin; Askerka, Mikhail; Brudvig, Gary W et al. (2017) Crystallographic Data Support the Carousel Mechanism of Water Supply to the Oxygen-Evolving Complex of Photosystem II. ACS Energy Lett 2:2299-2306|
|Greenlee, Etienne B; Stav, Shira; Atilho, Ruben M et al. (2017) Challenges of Ligand Identification for the Second Wave of Orphan Riboswitch Candidates. RNA Biol :0|
|Arachchilage, Gayan Mirihana; Sherlock, Madeline E; Weinberg, Zasha et al. (2017) SAM-VI RNAs Selectively Bind S-adenosylmethionine and Exhibit Similarities to SAM-III Riboswitches. RNA Biol :0|
Showing the most recent 10 out of 126 publications