A5077856838- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Viral Infections and Immunology Research
- RNA Interference and Gene Delivery
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- HIV Research and Treatment
- Autophagy in Disease and Therapy
- Amyotrophic Lateral Sclerosis Research
- Nanopore and Nanochannel Transport Studies
- Genomics and Chromatin Dynamics
- PARP inhibition in cancer therapy
- Molecular Biology Techniques and Applications
- Pancreatic function and diabetes
- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- Protein Structure and Dynamics
- Neurogenetic and Muscular Disorders Research
- Advanced NMR Techniques and Applications
- Electron Spin Resonance Studies
- Cellular transport and secretion
- Lipid metabolism and biosynthesis
- Molecular spectroscopy and chirality
- Heat shock proteins research
Johns Hopkins University
2020-2023
Duke University
2014-2023
Duke Medical Center
2014-2020
Duke University Hospital
2014-2020
Durham Technical Community College
2017
University of North Carolina at Chapel Hill
2014
Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is depletion RNA-binding protein TDP-43 from nucleus neurons in brain spinal cord 1 . major function as a repressor cryptic exon inclusion during RNA splicing 2–4 Single nucleotide polymorphisms UNC13A are among strongest hits associated with FTD ALS human genome-wide association studies 5,6 , but how those variants increase risk for disease...
Cellular energy influences all aspects of cellular function. Although cells can adapt to a gradual reduction in energy, acute depletion poses unique challenge. Because hampers the transport new sources into cell, cell must use endogenous substrates replenish after depletion. In yeast Saccharomyces cerevisiae, glucose starvation causes an intracellular that recovers during continued starvation. However, how replenishes early phase is unknown. this study, we investigated role pathways deliver...
NMR-guided evolution of the pyrazine C(5)- and C(6)-positions amiloride reveals a tunable scaffold for selective RNA interactions.
Poly(ADP-ribose) (PAR) is a homopolymer of adenosine diphosphate ribose that added to proteins as posttranslational modification regulate numerous cellular processes. PAR also serves scaffold for protein binding in macromolecular complexes, including biomolecular condensates. It remains unclear how achieves specific molecular recognition. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) evaluate flexibility under different cation conditions. We demonstrate that,...
Recent studies have shown that RNAs exist in dynamic equilibrium with short-lived low-abundance 'excited states' form by reshuffling base pairs and around non-canonical motifs. These conformational states are proposed to be rich motifs play roles the folding regulatory functions of non-coding but their structure proves difficult characterize given transient nature. Here, we describe an approach for determining sugar pucker conformation RNA excited through nuclear magnetic resonance...
Low-abundance short-lived non-native conformations referred to as excited states (ESs) are increasingly observed in vitro and implicated the folding biological activities of regulatory RNAs. We developed an approach for assessing relative abundance RNA ESs within functional cellular context. Nuclear magnetic resonance (NMR) spectroscopy was used estimate degree which substitution mutations bias conformational equilibria toward inactive ES vitro. The activity ES-stabilizing mutants indirect...
Abstract Sparse and short-lived excited RNA conformational states are essential players in cell physiology, disease, therapeutic development, yet determining their 3D structures remains challenging. Combining mutagenesis, NMR spectroscopy, computational modeling, we determined the structural ensemble formed by a (lifetime ~2.1 ms) lowly-populated (~0.4%) state HIV-1 TAR RNA. Through strand register shift, completely remodels structure of ground (RMSD from = 7.2 ± 0.9 Å), forming surprisingly...
RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) prevent fibrillization by promoting liquid phases, distinct and, remarkably, reverse condensation fibrillization. These activities require interactions multiple domains of are...
Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like minimize electrostatic and stacking interactions lead to nonspecific binding of aminoglycosides intercalators many stem–loop RNAs. Many such compounds have reported inhibit their activities. However, engagement selectivity assays are not routinely performed, it...
Fused in sarcoma (FUS) is a nuclear RNA-binding protein. Mutations FUS lead to the mislocalization of from nucleus cytosol and formation pathogenic aggregates neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) frontotemporal lobar dementia (FTLD), yet with unknown molecular mechanisms. Using mutant stress conditions, we visualized localization aggregate cells. We used single-molecule pull-down (SiMPull) quantify native oligomerization states wildtype (WT) demonstrate...
A viral tRNA-like structure has evolved a unique strategy to undergo tertiary conformational switch that may help regulate regulation.
Riboswitches are regulatory elements found in bacterial mRNAs that control downstream gene expression through ligand-induced conformational changes. Here, we used single-molecule FRET to map the landscape of translational SAM/SAH riboswitch and probe how co-transcriptional changes affect its translation regulation function. Riboswitch folding is highly heterogeneous, suggesting a rugged allows for sampling ligand-bound conformation even absence ligand. The addition ligand shifts landscape,...
Abstract Riboswitches are found in the 5’-UTR of many bacterial mRNAs. They function as cisacting regulatory elements that control downstream gene expression through ligand-induced conformational changes. Here, we used single-molecule FRET to map landscape SAM/SAH riboswitch and probe how co-transcriptional changes this translational switch alter ribosome accessibility. The folding is highly heterogenous, indicating a complex rugged enables sampling ligand-bound conformation even absence...
Poly(ADP-ribose) (PAR) is a homopolymer of adenosine diphosphate ribose that added to proteins as post-translational modification regulate numerous cellular processes. PAR also serves scaffold for protein binding in macromolecular complexes, including biomolecular condensates. It remains unclear how achieves specific molecular recognition. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) evaluate flexibility under different cation conditions. We demonstrate that,...
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