A5020422515- Signaling Pathways in Disease
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Peptidase Inhibition and Analysis
- Force Microscopy Techniques and Applications
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Lysosomal Storage Disorders Research
- Antifungal resistance and susceptibility
- Adenosine and Purinergic Signaling
- RNA Interference and Gene Delivery
- Advanced NMR Techniques and Applications
- Microbial metabolism and enzyme function
- Chemical Synthesis and Analysis
- Microfluidic and Bio-sensing Technologies
- Immunodeficiency and Autoimmune Disorders
- Enzyme function and inhibition
- Fuel Cells and Related Materials
- Autoimmune and Inflammatory Disorders Research
- Toxin Mechanisms and Immunotoxins
- MicroRNA in disease regulation
- thermodynamics and calorimetric analyses
- Electrospun Nanofibers in Biomedical Applications
- Ultrasound and Hyperthermia Applications
Pennsylvania State University
2017-2020
University of Kentucky
2013-2020
Lanmodulin (LanM) is a high-affinity lanthanide (Ln)-binding protein recently identified in Methylobacterium extorquens, bacterium that requires Lns for the function of at least two enzymes. LanM possesses four EF-hands, metal coordination motifs generally associated with CaII binding, but it undergoes metal-dependent conformational change 100 million-fold selectivity LnIIIs and YIII over CaII. Here we present nuclear magnetic resonance solution structure complexed YIII. This reveals...
The fungus Aspergillus fumigatus is a leading infectious killer in immunocompromised patients. Calcineurin, calmodulin (CaM)-dependent protein phosphatase comprised of calcineurin A (CnaA) and B (CnaB) subunits, localizes at the hyphal tips septa to direct A. invasion virulence. Here we identified novel serine-proline rich region (SPRR) located between two conserved CnaA domains, CnaB-binding helix CaM-binding domain, that evolutionarily unique filamentous fungi also completely absent human...
Calcineurin is an essential serine/threonine phosphatase that plays vital roles in neuronal development and function, heart growth, immune system activation. unique it the only known to be activated by calmodulin response increasing intracellular calcium concentrations. Calcium-loaded binds regulatory domain of calcineurin, resulting a conformational change removes autoinhibitory from active site phosphatase. We have determined 1.95 Å crystal structure bound peptide corresponding its binding...
The inability to spatiotemporally guide proteins in tissues and efficiently deliver them into cells remains a key barrier realizing their full potential precision medicine. Here, we report ultrasound-sensitive fluoro-protein nanoemulsions which can be acoustically tracked, guided, activated for on-demand cytosolic delivery of proteins, including antibodies, using clinically relevant diagnostic ultrasound. This advance is accessed through the discovery family fluorous tags, or FTags, that...
Calcineurin (CaN) is a calmodulin-activated, serine/threonine phosphatase that necessary for cardiac, vasculature, and nervous system development, as well learning memory, skeletal muscle growth, immune activation. CaN activated in manner similar to of the calmodulin (CaM)-activated kinases. CaM binds CaN's regulatory domain (RD) causes conformational change removes autoinhibitory (AID) from its catalytic site, activating CaN. In CaM-activated kinases, binding region (CaMBR) located just...
The pancreatic and duodenal homeobox 1 (Pdx1) is an essential transcription factor. C-terminal intrinsically disordered domain of Pdx1 (Pdx1-C) has a heavily biased amino acid composition; most notably, 18 83 residues are proline, including hexaproline cluster near the middle chain. For these reasons, Pdx1-C attractive target for structure characterization, given availability suitable methods. To determine solution ensembles proteins, we have developed suite 13C direct-detect NMR experiments...
Calcineurin is a Ser/Thr phosphatase that important for key biological processes, including immune system activation. We previously identified region in the intrinsically disordered regulatory domain of calcineurin forms critical amphipathic α-helix (the "distal helix") required complete activation calcineurin. This distal helix was shown to have Tm close human body temperature. Because determined dilute buffer, we hypothesized other factors inherent cellular environment might modulate...
Recent work has revealed that the association of a disordered region protein with folded binding partner can occur as rapidly between two proteins. This is case for phosphatase calcineurin (CaN) and its activator calmodulin. Calmodulin binds to intrinsically regulatory domain CaN. Previous studies have shown electrostatic steering accelerate proteins ligands. Given forces are strong determinants ensembles, relationship electrostatics, conformational quaternary interactions unclear. Here, we...
Intrinsically disordered proteins (IDPs) and with intrinsically regions (IDRs) govern a daunting number of physiological processes. For such proteins, molecular mechanisms governing their interactions involved in signal transduction pathways remain unclear. Using the folded, calcium-loaded calmodulin (CaM) interaction calcineurin regulatory IDP as prototype for IDP-mediated events, we uncover interplay structure electrostatic determining kinetics protein-protein association. an array...
A. fumigatus is one of the leading causes invasive fungal infections in solid organ transplant and adult stem cell recipients. It estimated that over 20% Americans are infected with T. gondii. gondii life threatening immunocompromised patients. Here, we study enzyme calcineurin critical for virulence pathogenicity these organisms. CaN activated when calcium‐loaded calmodulin ( CaM ) binds regulatory domain RD A subunit. Upon binding to CaM, human transitions from a disordered state an...
Background We have recently identified Niemann‐Pick type C2 (NPC2) protein as important regulator of somatic cell plasticity and inflammation (1,2). The latter unfolds in the setting NPC2‐deficiency is characterized by significant increase production secretion inflammatory mediators immune modulators including IL‐1β, IL‐6 prostaglandin E2 (1–3). Here we probed involvement NPC2 regulation innate immunity examining its role macrophage differentiation, polarization response human fibroblasts to...