A5031991802- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- Mitochondrial Function and Pathology
- Protein Kinase Regulation and GTPase Signaling
- Metalloenzymes and iron-sulfur proteins
- Chemical Synthesis and Analysis
- RNA modifications and cancer
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- Signaling Pathways in Disease
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Click Chemistry and Applications
- Machine Learning in Bioinformatics
- Parkinson's Disease Mechanisms and Treatments
- Malaria Research and Control
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- Phosphodiesterase function and regulation
- Tryptophan and brain disorders
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
University of Georgia
2015-2024
Georgia College & State University
2015-2021
Augusta University
2020
University of California, San Diego
2005-2009
Bloodworks Northwest
2002
Age-dependent bone loss occurs in humans and several animal species, including rodents. The underlying causal mechanisms are probably multifactorial, although an age-associated increase the generation of reactive oxygen species has been frequently implicated. We previously reported that aromatic amino acids function as antioxidants, anabolic for bone, they may potentially play a protective role aging environment. hypothesized upon oxidation would not only lose their effects but also become...
Phosphorylation of an evolutionarily conserved motif by mTORC2 enables the maturation AGC kinases.
Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are a leading cause of inherited form Parkinson's disease (PD), while LRRK2 overactivation is also associated with more common idiopathic PD. large multidomain protein, including GTPase as well Ser/Thr protein domain. Common, disease-causing mutations increase activity, presenting an attractive target drug discovery. Currently, development has mainly focused on ATP-competitive inhibitors. Here, we report identification and...
A-kinase anchoring proteins (AKAPs) play an important role in the spatial and temporal regulation of protein kinase A (PKA) by scaffolding critical intracellular signaling complexes. Here we report design conformationally constrained peptides that disrupt interactions between PKA AKAPs isoform-selective manner. Peptides derived from Kinase Binding (AKB) domain several were chemically modified to contain all-hydrocarbon staple target docking/dimerization PKA-R, thereby occluding AKAP...
Abstract Inactivation of the WASF3 gene suppresses invasion and metastasis breast cancer cells. function is regulated through a protein complex that includes NCKAP1 CYFIP1 proteins. Here, we report silencing destabilizes complex, resulting in suppression invasive capacity breast, prostate, colon In an vivo model spontaneous immunocompromized mice, loss also metastasis. Activation WASF occurs interaction with RAC1, inactivation prevents association RAC1 complex. Thus, depends on to promote...
Little is known about intracellular signaling mechanisms that persistently excite neurons in pain pathways. Persistent spontaneous activity (SA) generated the cell bodies of primary nociceptors within dorsal root ganglia (DRG) has been found to make major contributions chronic a rat model spinal cord injury (SCI) (Bedi et al., 2010; Yang 2014). The occurrence SCI-induced SA large fraction DRG and persistence this long after dissociation provide an opportunity define intrinsic chronically...
Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), second most commonly occurring neurodegenerative disorder worldwide. We recently reported development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption dimerization. In this study, we designed doubly peptides with objective inhibiting C-terminal Roc (COR)–COR mediated dimerization at dimer interface. show...
Aurora-A regulates the recruitment of TACC3 to mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe structural basis these interactions, mediated by three motifs in disordered region TACC3. A hydrophobic docking motif binds previously uncharacterized pocket on that is blocked most kinases. Abrogation causes delay late mitosis, consistent cellular distribution complexes. Phosphorylation Ser558 engages conformational switch second from...
Abstract Activation of the WASF3 protein by extracellular stimuli promotes actin cytoskeleton reorganization and facilitates cancer cell invasion, whereas depletion suppresses invasion metastasis. In quiescent cells, interaction between a complex proteins, including CYFIP1, acts as conformational restraint to prevent activation. Therefore, we took advantage this endogenous regulatory mechanism investigate potential sites that disrupt function. Here, show genetic knockdown CYFIP1 in cells led...
Protein tyrosine kinases (PTKs) are a group of closely related enzymes that have evolutionarily diverged from serine/threonine (STKs) to regulate pathways associated with multi-cellularity. Evolutionary divergence PTKs STKs has occurred through accumulation mutations in the active site as well commonly conserved hydrophobic core. While functional significance variations is understood, relatively little known about how core contribute PTK evolutionary divergence. Here, using combination...
Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein with dual kinase and GTPase function that commonly mutated in both familial idiopathic Parkinson's Disease (PD). While dimerization of LRRK2 detected PD models, it remains unclear whether inhibition can regulate catalytic activity pathogenesis. Here, we show constrained peptides are cell-penetrant, bind LRRK2, inhibit activation by downregulating dimerization. We further inhibited decreases inhibits ROS production PD-linked...
Streptococcus pneumoniae is one of the world's foremost bacterial pathogens, with extensive serotype diversity that impacted efficacy current vaccines. Our group have previously reported generation a whole cell serotype-independent gamma-irradiated pneumococcal vaccine (Gamma-PN). The present study sought to compare effect gamma-irradiation, heat, ethanol, or formalin inactivation on antigenic structure and immunogenicity whole-cell data demonstrate Gamma-PN exhibited comparable cellular...
Protein kinase A holoenzyme is comprised of two catalytic (C) and regulatory (R) subunits which keep the enzyme in an inhibited state before activation by cyclic-AMP. The C-subunit folds into a conserved bi-lobal core flanked N- C-terminal tails. We report here characterization C-tail loss-of-function mutant, CF327A, related suppressor CF327A/K285P. Phe-327 only residue outside that binds to adenine ring ATP, whereas Lys-285 approximately 45 away lies AGC kinase-specific insert. mutations...
A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora diverse pathways, their cellular roles are often elusive due to the dynamic nature these complexes. can interact with type I or II PKA holoenzymes virtue high-affinity interactions R-subunits. As means delineate AKAP-mediated cells, we sought develop isoform-selective disruptors AKAP signaling....
The epidermal growth factor receptor (EGFR) is overexpressed in multiple carcinomas and the focus of a variety targeted therapies. Here we report design peptide-based compounds that mimic EGFR dimerization arm inhibit allosteric activation EGFR. These peptides are modified to contain triazolyl bridge between peptide strands constrain β-loop. In this study, demonstrate these have significantly improved proteolytic stability over non-modified sequence, their inhibitory effects dependent on...
A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools increase specificity signalling. Here, we elucidated structure an extended PKA-binding domain AKAP18β bound D/D RIIα PKA. We identified three hydrophilic anchor points in outside core domain, which mediate contacts domain. Such are conserved within that bind RII derived...
The WASF3 gene facilitates the metastatic phenotype, and its inactivation leads to suppression of invasion metastasis regardless genetic background cancer cell. This reliance on facilitate suggests that targeting function could serve as an effective strategy suppress metastasis. stability are regulated by WASF Regulatory Complex (WRC) proteins, particularly CYFIP1 NCKAP1. Knockdown these proteins in vitro disruption WRC invasion. We have used mouse xenograft models breast assess whether...
ABSTRACT Extracellular nucleotides play many biological roles, including intercellular communication and modulation of nucleotide receptor signaling, are dependent on the phosphorylation state nucleotide. Regulation is necessary, a specialized class enzymes, pyrophosphatases/phosphodiesterases (E-NPPs), has been identified in mammals to perform this function. Although E-NPP conserved among complex eukaryotes, system not yet Saccharomyces cerevisiae. Using genetic biochemical experiments, we...