A5088629909- Heat shock proteins research
- Genetics, Aging, and Longevity in Model Organisms
- Endoplasmic Reticulum Stress and Disease
- Prion Diseases and Protein Misfolding
- Protein Structure and Dynamics
- Genetic Neurodegenerative Diseases
- Amyotrophic Lateral Sclerosis Research
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Fungal and yeast genetics research
- Enzyme Structure and Function
- Coenzyme Q10 studies and effects
- Proteins in Food Systems
- RNA and protein synthesis mechanisms
- Neurogenetic and Muscular Disorders Research
- Viral Infectious Diseases and Gene Expression in Insects
- Parkinson's Disease Mechanisms and Treatments
- Glycosylation and Glycoproteins Research
- Immunotherapy and Immune Responses
- RNA modifications and cancer
- Nuclear Structure and Function
- Electron and X-Ray Spectroscopy Techniques
- Neuroinflammation and Neurodegeneration Mechanisms
- Phagocytosis and Immune Regulation
- Advanced Electron Microscopy Techniques and Applications
Washington University in St. Louis
2019-2025
University of Pennsylvania
2012-2023
Meredith College
2021
Philadelphia University
2014-2015
Yale University
2009
Untangling aggregates one step at a time Conserved AAA+ protein complexes exploit adenosine triphosphate hydrolysis to unfold and disaggregate their substrates in response cell stress, but exactly how they do this has been unclear. Gates et al. determined high-resolution cryo-electron microscopy structures of the Hsp104 disaggregase bound an unfolded polypeptide substrate its channel. The reveal interactions two different translocation states. undergoes conformational changes that drive...
Cytoplasmic inclusions of the RNA-binding protein fused in sarcoma (FUS) represent one type membraneless ribonucleoprotein compartment. Formation FUS is promoted by amyotrophic lateral sclerosis (ALS)–linked mutations, but cellular functions affected upon inclusion formation are poorly defined. In this study, we find that lead to mislocalization specific RNAs from fibroblast cell protrusions and neuronal axons. This mediated recruitment kinesin-1 mRNA within inclusions, leading a loss...
Abstract Parkinson’s disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which associated with Alzheimer’s disease, inactivating mutations mitochondrial HTRA2 are implicated PD. Here, we report that inhibits aggregation of α-syn as well FUS TDP-43, amyotrophic lateral sclerosis (ALS) frontotemporal dementia. domain necessary sufficient for inhibiting aggregation, yet this activity...
Abstract Protein misfolding is implicated in numerous lethal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD). There are no therapies that reverse these protein-misfolding events. We aim to apply Hsp104, a hexameric AAA+ protein from yeast, target misfolded conformers for reactivation. Hsp104 solubilizes disordered aggregates amyloid, but has limited activity against human proteins. Thus, we have previously engineered potentiated variants...
Abstract Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD- UMOD ), a leading hereditary disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD- carrying mutation, we show that autophagy/mitophagy and mitochondrial biogenesis impaired, cGAS-STING activation tubular injury. Moreover, demonstrate inducible overexpression of mesencephalic...
Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), distal myopathy. Here, we report the development of yeast model MATR3 proteotoxicity aggregation. toxic forms dynamic shell-like nuclear condensates yeast. Disease-associated mutations impair condensate dynamics disrupt morphology. toxicity largely driven by its RNA-recognitions motifs (RRMs). Further, deletion one or both RRMs drives coalescence these...
Peptides and peptidomimetics that self-assemble through LLPS have recently emerged as vital building blocks for creating functional biomaterials, thanks to their unique physicochemical properties dynamic nature. One of life's most distinctive features is its selectivity chiral molecules. To date, coacervates comprised d-amino acids not been reported. Here, we demonstrate histidine-rich repeats (GHGXY)4 (X = L/V/P) enantiomers undergo LLPS, paving the way improved coacervate stability....
Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2–3 subunits hexamer must bear an A503V potentiating mutation elicit enhanced activity in absence Hsp70. We also define ATPase substrate-binding modalities needed for potentiated Hsp104A503V vitro...
Hsp104 is a hexameric AAA + ATPase and protein disaggregase found in yeast, which can be potentiated via mutations its middle domain (MD) to counter toxic phase separation by TDP-43, FUS α-synuclein connected devastating neurodegenerative disorders. Subtle missense the MD enhance activity, indicating that post-translational modification of specific residues might also potentiate Hsp104. Indeed, several serine threonine throughout phosphorylated vivo. Here, we introduce phosphomimetic...
Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated fatal neurodegenerative disorders. Problematically, MD variants exhibit off-target toxicity. Here, we mine disaggregase sequence space safely enhance activity single nucleotide-binding 1 (NBD1) or NBD2. Like variants, NBD counter toxicity elevated ATPase activity. Unlike non-toxic NBD1 NBD2...
Designer protein modules, which bind specifically to a desired target, have numerous potential applications. One approach creating such proteins is construct and screen libraries. Here we present detailed description of using split-GFP reassembly assay libraries identify with novel binding properties. Attractive features the based are absence false positives simplicity, robustness, ease automation screen. Here, describe both construction naive library, screening library that chosen peptide sequences.
Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense at 20 different positions interspersed throughout the middle domain (MD) small of nucleotide-binding 1 (NBD1) confer therapeutic gain Hsp104 function. Moreover, potentiation emerges deletion MD helix 3 4 via...
Aberrant protein folding is severely problematic and manifests in numerous disorders, including amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington (HD), Alzheimer (AD). Patients with each of these disorders are characterized by the accumulation mislocalized deposits. Treatments for remain palliative, no available therapeutics eliminate underlying toxic conformers. An intriguing approach to reverse deleterious misfolding upregulate chaperones restore proteostasis. We...
The small subunit (SSU) processome is a ribosome biogenesis intermediate that assembles from its subcomplexes onto the pre-18S rRNA with yet unknown order and structure. Here, we investigate architecture of UtpB subcomplex SSU processome, focusing on interaction between half-a-tetratricopeptide repeat (HAT) domain Utp6 specific peptide in Utp21. We present comprehensive map interactions within further show N-terminal interacts Utp18 while HAT Using panel point deletion mutants Utp6, an...