A5047849537- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Autophagy in Disease and Therapy
- Muscle Physiology and Disorders
- Genetics, Aging, and Longevity in Model Organisms
- Alzheimer's disease research and treatments
- Amyotrophic Lateral Sclerosis Research
- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Signaling Pathways in Disease
- Cannabis and Cannabinoid Research
- Insect Resistance and Genetics
- Spaceflight effects on biology
- Cancer, Hypoxia, and Metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Epigenetics and DNA Methylation
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- 14-3-3 protein interactions
Duke University
2019-2025
Medical College of Wisconsin
2013-2020
Saint Louis University
2003-2016
University of Michigan
2008-2014
University of South Florida
2012
Aggregation of tau protein in the brain is associated with a class neurodegenerative diseases known as tauopathies. FK506 binding 51 kDa (FKBP51, encoded by FKBP5) forms mature chaperone complex Hsp90 that prevents degradation. In this study, we have shown levels are reduced throughout brains Fkbp5-/- mice. Recombinant FKBP51 and synergized to block clearance through proteasome, resulting oligomerization. Overexpression transgenic mouse model revealed preserved species been linked...
Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves chains manner suggesting it functions as mixed linkage, chain-editing enzyme. Ataxin-3 through its amino-terminal Josephin domain carboxyl-terminal cluster interaction motifs neighboring pathogenic tract. both Lys48- or Lys63-linked yet preferentially Lys63 linkages....
Attachment of ubiquitin to substrate is typically thought occur via formation an isopeptide bond between the C-terminal glycine residue and a lysine in substrate. In vitro, Ube2w nonreactive with free yet readily ubiquitinates also contains novel residues within its active site that are important for ability ubiquitinate To identify modification, we analyzed ubiquitinated substrates by mass spectrometry found N-terminal -NH2 group as conjugation. confirm ubiquitination, generated lysine-less...
Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight into the mechanism by which ubiquitination directly enhances activity of ataxin-3, a DUb implicated protein quality control and disease polyglutamine neurodegenerative disorder, Spinocerebellar Ataxia Type 3. We identify Lys-117, resides near catalytic triad, as primary site wild type pathogenic ataxin-3. Further...
The microtubule associated protein tau (MAPT/tau) aberrantly accumulates in 15 neurodegenerative diseases, termed tauopathies. One way to treat tauopathies may be accelerate clearance, but the molecular mechanisms governing stability are not yet clear. We recently identified chemical probes that markedly clearance of cellular and animal models. In current study, we used one these combination with immunoprecipitation mass spectrometry identify 48 proteins whose association changes during...
Deubiquitinases (DUBs) are proteases that regulate various cellular processes by controlling protein ubiquitination. Cell-based studies indicate the regulation of activity DUBs is important for homeostasis and achieved multiple mechanisms, including through their own However, physiological significance ubiquitination to functions in vivo unclear. Here, we report DUB ataxin-3 at lysine residue 117, which markedly enhances its protease vitro, critical ability suppress toxic protein-dependent...
The E3 ubiquitin ligase CHIP (C-terminus of Hsc70 Interacting Protein, a 70 kDa homodimer) binds to the molecular chaperone (a monomer), and this complex is important in both ubiquitination turnover Hsc70-bound clients. Here we used NMR spectroscopy, biolayer interferometry, fluorescence polarization characterize Hsc70–CHIP interaction. We found that tightly two molecules forming 210 complex, with Kd approximately 60 nM, IEEVD motif at C-terminus (residues 642–646) necessary sufficient for...
Post-translational modifications are critical for regulating the RIG-I signaling pathway. Previously, we identified a role post-translation modification UFM1 (UFMylation) in promoting by stimulating interaction between and its membrane-targeting protein 14-3-3ϵ. Here, identify UFMylation of 14-3-3ϵ as novel regulatory mechanism signaling. We demonstrate that conjugation to lysine residue K50 or K215 results mono-UFMylation on enhances ability promote Importantly, show mutation these residues...
Polyglutamine (polyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration Spinocerebellar Ataxia Type 3 (SCA3), one of nine inherited, incurable diseases caused by similar mutations. Ataxin-3's degradation is inhibited its binding to proteasome shuttle Rad23 through ubiquitin-binding site 2 (UbS2). Disrupting this interaction decreases levels ataxin-3. Since reducing polyQ proteins can decrease their toxicity, we tested whether genetically modulating ataxin-3-Rad23...
The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract accumulation, neurons have pathways that recognize refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus Hsc70-interacting (CHIP), plays a key role this process, targeting for proteasomal degradation. CHIP protective mouse models disease, humans, mutations cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16),...
The expression, misfolding, and aggregation of long repetitive amino acid tracts are a major contributing factor in number neurodegenerative diseases, including C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia, fragile X tremor ataxia syndrome, myotonic dystrophy type 1, spinocerebellar 8, the nine polyglutamine diseases. Protein is hallmark each these In model organisms, yeast, worms, flies, mice, rats, human cells, expression proteins with associated diseases recapitulates...
Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that specifically cleaves poly-ubiquitin chains and participates in ubiquitin proteasome pathway. The enzymatic activity resides N-terminal Josephin domain. An unusual feature of ataxin-3 its low especially mono-ubiquitinated substrates short chains. However, specific ubiquitination at lysine 117 domain activates through an unknown mechanism. Here, we investigate effects K117 on structure protein. We...
Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum disease, complicating treatment options. Spinocerebellar autosomal recessive 16 (SCAR16) is caused coding mutations STUB1, gene encodes multifunctional enzyme CHIP (C terminus HSC70-interacting protein). The disease SCAR16 includes varying age onset, cognitive dysfunction, increased tendon reflex, hypogonadism. Although span...
One of the several still unexplained aspects mechanism by which Cdc34/SCF RING-type ubiquitin ligases work is marked stimulation Cdc34 autoubiquitination, a phenomenon unknown and significance. In in vitro experiments with single-lysine-containing mutant proteins Saccharomyces cerevisiae, we found that SCF-mediated autoubiquitination limited to specific N-terminal lysines modified via an intermolecular mechanism. striking contrast, SCF quenches C-terminal catalyzed intramolecular manner....