A5039861245- Protein Tyrosine Phosphatases
- ATP Synthase and ATPases Research
- Macrophage Migration Inhibitory Factor
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Protein Kinase Regulation and GTPase Signaling
- Endoplasmic Reticulum Stress and Disease
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- Microtubule and mitosis dynamics
- Alkaline Phosphatase Research Studies
- Cellular transport and secretion
- RNA Research and Splicing
- Cancer-related Molecular Pathways
- Digestive system and related health
- RNA and protein synthesis mechanisms
- Calpain Protease Function and Regulation
- Peptidase Inhibition and Analysis
- Metabolism and Genetic Disorders
- Carbohydrate Chemistry and Synthesis
- Autophagy in Disease and Therapy
- Enzyme function and inhibition
- Antifungal resistance and susceptibility
- Glycogen Storage Diseases and Myoclonus
UConn Health
2023-2024
University of Arizona
2017-2020
Brown University
2012-2017
Duke-NUS Medical School
2011
National University of Singapore
2004-2010
United States Department of Veterans Affairs
1979
University of California, San Francisco
1979
The attenuation of protein synthesis via the phosphorylation eIF2α is a major stress response all eukaryotic cells. growth-arrest- and DNA-damage-induced transcript 34 (GADD34) bound to serine/threonine phosphatase 1 (PP1) necessary complex that returns mammalian cells normal following stress. molecular basis by which GADD34 recruits PP1 its substrate are not fully understood, hindering our understanding remarkable selectivity GADD34:PP1 for eIF2α. Here, we report detailed structural...
The serine/threonine protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. However, how these direct PP1 specificity and the ability predict interacting bind from sequence alone is still missing. nuclear targeting subunit (PNUTS) a that, PP1, plays central role in nucleus, where it regulates chromatin decondensation, RNA processing, phosphorylation state fundamental cell cycle...
The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some symptoms; hence, more effective therapeutic strategies needed. We identified the tyrosine phosphatase PTP1B as candidate of RTT. demonstrated that PTPN1 gene, which encodes PTP1B, was target MECP2 disruption function associated...
Abstract To achieve substrate specificity, protein phosphate 1 (PP1) forms holoenzymes with hundreds of regulatory and inhibitory proteins. Inhibitor-3 (I3) is an ancient inhibitor PP1 putative roles in maturation the regulation activity. Here, we show that I3 residues 27–68 are necessary sufficient for binding inhibition. In addition to a canonical RVxF motif, which shared by nearly all regulators inhibitors, non-canonical SILK also binds via multiple basic bind directly acidic groove,...
Abstract Although inhibition of the ubiquitin proteasome system has been postulated to play a key role in pathogenesis neurodegenerative diseases, studies have also shown that can induce increased expression neuroprotective heat‐shock proteins (HSPs). The global gene primary neurons response treatment with inhibitor lactacystin was studied identify widest range possible pathways affected. Our results showed changes mRNA abundance, both at different time points after and concentrations. Genes...
Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and guide drug development. Biologically diverse organisms (e.g., cyanobacteria, dinoflagellates, beetles) produce structurally distinct toxins that catalytic PPPs. However, most exhibit little selectivity, typically inhibiting multiple family members with similar potencies. Thus, use these as chemical tools study relationship between individual their substrates, how...
Abstract Penicillin-binding proteins (PBPs) are essential for the formation of bacterial cell wall. They also targets β-lactam antibiotics. In Enterococcus faecium , high levels resistance to β-lactams associated with expression PBP5, higher distinct PBP5 variants. To define molecular mechanism PBP5-mediated we leveraged biomolecular NMR spectroscopy – due its size (>70 kDa) a challenging target. Our data show that resistant variants significantly increased dynamics either alone or upon...
The integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases dephosphorylate it. Genetic biochemical observations indicate eIF2αP-directed holophosphatase, a therapeutic target in diseases protein misfolding, comprised regulatory subunit, PPP1R15, catalytic phosphatase 1 (PP1). In mammals, there are two isoforms PPP1R15A PPP1R15B, with overlapping roles essential function eIF2αP dephosphorylation. However,...
The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, regulated by scores regulatory proteins, including the highly conserved SDS22 protein. has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and an activator. Here, we integrate cellular, biophysical, crystallographic studies to address this conundrum. We discovered that selectively binds unique conformation contains single metal (M2) at its active site,...
Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm membranes, with their membrane association showing similar biochemical properties. Deletion of N-terminal sequences GADD34-GFP highlighted an amphipathic helix, whose hydrophobic surface, specifically valine 25 leucine 29, mediated endoplasmic reticulum (ER) localization. Substitution leucines for three arginines on polar surface indicated that same helix also mitochondria. Fluorescence...
Specific substrate recruitment by the protein phosphatase-1 molecule G subunit holoenzyme enables maintenance of glucose levels.
A "tug-of-war" between kinases and phosphatases establishes the phosphorylation states of proteins. While serine threonine can be catalyzed by more than 400 protein kinases, majority dephosphorylation is carried out seven phosphoprotein (PPPs). The PPP family consists 1 (PP1), 2A (PP2A), 2B (PP2B), 4 (PP4), 5 (PP5), 6 (PP6), 7 (PP7). imbalance in numbers serine- threonine-directed led to early belief that PPPs are unspecific primary determinants phosphorylation. However, it now clear achieve...
Programmed cell death (PCD), is a highly regulated and sophisticated cellular mechanism that commits to isolated fate. PCD has been implicated in the pathogenesis of numerous neurodegenerative disorders. Countless molecular events underlie this phenomenon, with each playing crucial role commitment. A precedent event, apoptotic volume decrease (AVD), ubiquitously observed various forms induced by different insults. Under physiological conditions, cells when subjected osmotic fluctuations will...
ABSTRACT The opportunistic pathogen Candida is one of the most common causes nosocomial bloodstream infections. Because candidemia associated with high mortality rates and because incidences multidrug-resistant are increasing, efforts to identify novel targets for development potent antifungals warranted. Here, we describe structure function first member a family protein phosphatases that specific fungi, phosphatase Z1 (PPZ1) from albicans . We show PPZ1 not only active but also as...
Phosphoprotein phosphatases (PPPs) are the key serine/threonine that regulate all essential signaling cascades. In particular, Protein Phosphatase 1 (PP1) dephosphorylates ~80% of ser/thr phosphorylation sites. Here, we developed a phosphatase targeting peptide (PhosTAP) binds PP1 isoforms and does so with stronger affinity than any other known regulator. This PhosTAP can be used as recruitment tool for Phosphorylation Targeting Chimera (PhosTAC)-type in vitro cellular experiments, well...
Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. We others demonstrated that treatment cortical neurons with the proteasomal inhibitor lactacystin leads apoptosis. discovered by microarray analysis modulates expression both potentially neuroprotective well pro-apoptotic genes neurons. However, significance which upon transcriptional modulation contributed...
Ebola virus (EBOV) is a non-segmented negative-sense RNA that causes severe human disease. The ongoing EBOV outbreak in the Eastern part of Democratic Republic Congo has resulted to date over 2000 confirmed cases including 1000 deaths. Difficulties with vaccine administration indicate necessity for development new general drugs and therapeutic strategies against EBOV. Host Ser/Thr protein phosphatases, particularly PP1 PP2A, facilitate transcription by dephosphorylating VP30 switching...