A5066084028- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- MicroRNA in disease regulation
- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Genomics and Rare Diseases
- Protein Structure and Dynamics
- interferon and immune responses
- CRISPR and Genetic Engineering
- Autism Spectrum Disorder Research
- Viral Infections and Immunology Research
- ATP Synthase and ATPases Research
Office of Extramural Research
2024
National Institute of Diabetes and Digestive and Kidney Diseases
2024
Johns Hopkins University
2024
National Heart Lung and Blood Institute
2023-2024
National Institutes of Health
2023-2024
Max Planck Institute for Molecular Genetics
2011-2016
Max Planck Society
2011
Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females 2 males a de novo variant CLCN4 (6 previously unreported) 27 males, 3 15 asymptomatic female carriers 9 inherited variants (4 unreported). Intellectual ranged borderline profound....
The polyglutamine-binding protein 1 (PQBP1) has been linked to several X-linked intellectual disability disorders and progressive neurodegenerative diseases. While it is currently known that PQBP1 localizes in nuclear speckles engaged transcription splicing, we have now identified a cytoplasmic pool of PQBP1. Analysis complexes revealed six novel interacting proteins, namely the RNA-binding proteins KSRP, SFPQ/PSF, DDX1 Caprin-1, two subunits intracellular transport-related dynactin complex,...
The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated (NMD). Structural biochemical data have revealed that exists in an enzymatically autoinhibited 'closed' state. Upon binding NMD protein UPF2, undergoes extensive conformational change into a more active 'open' state, which exhibits enhanced ATPase activity. However, mechanically deficient mutants (i.e. poorly processive, slow, mechanochemically uncoupled) can support...
Abstract Many microRNA (miRNA)-guided Argonaute proteins can cleave RNA (‘slicing’), even though miRNA-mediated target repression is generally cleavage-independent. Here we use Caenorhabditis elegans to examine the role of catalytic residues miRNA Argonautes in organismal development. In contrast previous work, mutations presumed did not interfere with development when introduced by CRISPR. We find that unwinding and decay star strands weakly defective residue mutants, largest effect...
Abstract The conserved TRIM-NHL protein, NHL-2, plays a key role in small RNA pathways Caenorhabditis elegans . NHL-2 has been shown to interact with U-rich through its NHL domain, but the importance biological function is unknown. We defined crystal structure of domain 1.4 Å resolution and identified residues that affect affinity for RNA. Functional analysis an RNA-binding loss-of-function mutant demonstrated defects heterochronic pathway, suggesting binding essential this miRNA pathway....
Abstract The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated (NMD). Structural biochemical data have revealed that exists in an enzymatically autoinhibited “closed” state. Upon binding NMD protein UPF2, undergoes extensive conformational change into a more active “open” state, which exhibits enhanced ATPase activity. However, mechanically deficient mutants can support efficient NMD, bringing question roles of enzymatic...