A5052887835- Protein Structure and Dynamics
- Hippo pathway signaling and YAP/TAZ
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- RNA Research and Splicing
- Cancer, Hypoxia, and Metabolism
- Chemical Synthesis and Analysis
- Heat shock proteins research
- Advanced NMR Techniques and Applications
- Macrophage Migration Inhibitory Factor
- Retinal Diseases and Treatments
- Cellular transport and secretion
- Erythrocyte Function and Pathophysiology
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- Adipose Tissue and Metabolism
- NMR spectroscopy and applications
- Nuclear Receptors and Signaling
- Mass Spectrometry Techniques and Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Microbial Natural Products and Biosynthesis
- Genomics and Chromatin Dynamics
- Renal Diseases and Glomerulopathies
- Protein Kinase Regulation and GTPase Signaling
- Biochemical and Structural Characterization
University of North Carolina at Chapel Hill
2022-2024
Scripps Research Institute
2014-2023
Scripps Institution of Oceanography
2020
Yale University
2007-2012
Whitney Museum of American Art
2007-2012
Columbia University
2007
Significance Intrinsically disordered proteins must frequently compete for binding to shared interaction hubs perform their cellular functions. Here, we describe the mechanism by which two that regulate transcriptional response hypoxia folded TAZ1 domain of coactivators CBP and p300. CITED2, a negative feedback regulator HIF-1α, displaces HIF-1α from in unidirectional, switch-like manner. Efficient competition is highly dependent on flexibility multivalency CITED2 activation domains....
Significance Retinal ischemia causes hypoxia-induced neovascularization that stimulates production of proangiogenic cytokines such as VEGF by the hypoxia-inducible transcription factors HIF-1 and HIF-2. Current therapies for ischemic retinal diseases target circulating but do not modulate activity control its production. We demonstrate inhibiting HIF-mediated with a peptide derived from intrinsically disordered protein CITED2, negative feedback regulator HIF-1α, reduces pathological...
The intrinsically disordered transactivation domains of HIF-1α and CITED2 compete for binding the TAZ1 domain CREB-binding protein by a unidirectional allosteric mechanism involving direct competition shared sites, ternary complex formation, conformational changes. To gain insight into which displaces from TAZ1, we used nuclear magnetic resonance spin relaxation methods to obtain an atomic-level description picosecond nanosecond backbone dynamics that contribute competition. We show adopt...
The enzyme triosephosphate isomerase (TIM) has been used as a model system for understanding the relationship between protein sequence, structure, and biological function. sequence of active site loop (loop 6) in TIM is directly correlated with conserved motif 7. Replacement 7 chicken corresponding from an archaeal homologue caused 10(2)-fold loss enzymatic activity, decrease substrate binding affinity, thermal stability. Isotope exchange studies performed by one-dimensional (1)H NMR showed...
Abstract Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it known that retinal microglia contribute to both physiological and pathological angiogenesis, molecular mechanisms by which these glia regulate NV have not been fully elucidated. In this study, we utilized a microglia‐specific Transforming Growth Factor‐β (Tgfβ) receptor knock out mouse model human iPSC‐derived examine role Tgfβ signaling activated during...
The cyclic AMP response element (CRE) binding protein (CREB) is a transcription factor that contains 280-residue N-terminal transactivation domain and basic leucine zipper mediates interaction with DNA. comprises three subdomains, the glutamine-rich domains Q1 Q2 kinase inducible activation (KID). NMR chemical shifts show isolated subdomains are intrinsically disordered but have propensity to populate local elements of secondary structure. exhibit for formation short β-hairpin motifs...
The motion of the active site loop (loop 6) in triosephosphate isomerase is investigated solution by TROSY NMR spin-relaxation experiments. data show clear evidence for with an exchange rate constant (kex) 9000 s-1, consistent opening and closing this being partially rate-limiting to catalytic throughput. Similar constants are observed residues both N- C-terminal regions 6, suggesting motional coupling hinges. Mutation tyrosine 208 a phenylalanine (Y208F) eliminates hydrogen bond closed...
A model system of peptidomimetics was developed to characterize the complex conformational ensembles compositionally identical disordered peptoids using a suite analyses, including rapid colorimetric technique.
Understanding how a macromolecule’s primary sequence governs its conformational landscape is crucial for elucidating function, yet these design principles are still emerging macromolecules with intrinsic disorder. Herein, we introduce high-throughput workflow that implements practical colorimetric assay, introduces semi-automated sequencing protocol using MALDI-MS/MS, and develops generalizable sequence-structure algorithm. Using model system of 20mer peptidomimetics containing polar glycine...
Understanding how a macromolecule’s primary sequence governs its conformational landscape is crucial for elucidating function, yet these design principles are still emerging macromolecules with intrinsic disorder. While parameters describing subsets of disordered proteins and synthetic materials have been established, they often tailored to specific chemical interactions monomer classes, limiting their broader applicability. To address this gap, we present high-throughput workflow that...
While the conformational ensembles of disordered peptides and peptidomimetics are complex challenging to characterize, they a critical component in paradigm connecting macromolecule sequence, structure, function. In molecules that do not adopt single predominant conformation, ensemble contains rich structural information that, if accessible, can provide fundamental understanding related desirable functions such as cell penetration therapeutic or generation tunable enzyme-mimetic...