A5100406967- Selenium in Biological Systems
- Trace Elements in Health
- Endoplasmic Reticulum Stress and Disease
- Protease and Inhibitor Mechanisms
- Machine Learning in Bioinformatics
- Infant Nutrition and Health
- Protein Structure and Dynamics
- Heat shock proteins research
- Clinical Nutrition and Gastroenterology
- Microbial Metabolites in Food Biotechnology
- Bacterial Genetics and Biotechnology
- Genomics and Rare Diseases
- Multiple Myeloma Research and Treatments
- Blood Coagulation and Thrombosis Mechanisms
- Enzyme Production and Characterization
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Respiratory Support and Mechanisms
- Protein Degradation and Inhibitors
- Food composition and properties
- Toxin Mechanisms and Immunotoxins
- Biochemical and Structural Characterization
- Organoselenium and organotellurium chemistry
- Escherichia coli research studies
- Seed and Plant Biochemistry
Scripps Research Institute
2015-2025
Shenzhen Bay Laboratory
2025
Scripps (United States)
2019-2024
Scripps Institution of Oceanography
2019-2024
China Agricultural University
2024
Chinese National Human Genome Center at Shanghai
2024
Jiangsu University
2024
Zhejiang University-University of Edinburgh Institute
2023-2024
Southwest Forestry University
2023
State Forestry and Grassland Administration
2023
Aim: Human protein disulfide isomerase (hPDI) is a key enzyme and redox-regulated chaperone responsible for oxidative folding in the endoplasmic reticulum. This work aims to reveal molecular mechanism underlying functions of hPDI by determining crystal structures different redox states. Results: The (abb′xa′) both reduced oxidized states showed that four thioredoxin domains a, b, b′, a′ are arranged as horseshoe shape with two CGHC active sites, respectively, facing each other at ends. In...
Protein-disulfide isomerase (PDI), with domains arranged as abb'xa'c, is a key enzyme and chaperone localized in the endoplasmic reticulum (ER) catalyzing oxidative folding preventing misfolding/aggregation of proteins. It has been controversial whether activity PDI redox-regulated, molecular basis unclear. Here, we show that both overall conformation human are redox-regulated. We further demonstrate conformational changes triggered by active site domain a', minimum redox-regulated cassette...
Protein disulfide isomerase (PDI), which consists of multiple domains arranged as abb'xa'c, is a key enzyme responsible for oxidative folding in the endoplasmic reticulum. In this work we focus on conformational plasticity enzyme. Proteolysis native human PDI (hPDI) by several proteases consistently targets sites C-terminal half molecule (x-linker and a' domain) leaving large fragments N terminus intact. Fluorescence studies W111F/W390F mutant full-length show that its fluorescence dominated...
CREB (cyclic-AMP responsive element binding protein) protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of series 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led compound 9g (Y08284), which possesses good liver microsomal stability pharmacokinetic properties (F = 25.9%). Furthermore, able inhibit well proliferation,...
Highlights•HTS discovers nutraceutical compounds MPTC and PEITC that restore function in AATD•MPTC regulate cellular redoxstasis to AATD through PDIA4•GP-SCV machine learning captures residue-by-residue responses of AAT MPTC/PEITC•GP-SCV provides an atomic-resolution description regulation AATDSummaryAlpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding variants resulting gain-of-toxic aggregation the liver loss monomer activity lung leading chronic...
Highlights•We develop VSP, a Gaussian-process-based approach to interpret genomic diversity•VSP is based on spatial covariance (SCV) in the genotype-to-phenotype transformation•SCV uses population genomics inform individualized phenotypes at atomic resolution•Phenotype landscapes generated through SCV enable high-definition medicineSummaryTo understand impact of genome sequence variation (the genotype) responsible for biological diversity and human health phenotype) including cystic fibrosis...
Owing to the strong antioxidant capacity of selenium (Se) in vivo, a variety Se compounds have been shown great potential for improving main pathologies and cognitive impairment Alzheimer's disease (AD) models. However, differences anti-AD effects mechanisms different are still unclear. Theoretically, absorption metabolism forms body vary, which directly determines diversification downstream regulatory pathways. In this study, low doses Se-methylselenocysteine (SMC), selenomethionine (SeM),...
Protein disulfide isomerase (PDI) composed of four thioredoxin-like domains a, b, b', and a', is a key enzyme catalyzing oxidative protein folding in the endoplasmic reticulum. Large scale molecular dynamics simulations starting from crystal structures human PDI (hPDI) oxidized reduced states were performed. The results indicate that hPDI adopts more compact conformations solution than structures, which are stabilized primarily by inter-domain interactions, including salt bridges between b'...
Abstract Genetic diversity provides a rich repository for understanding the role of proteostasis in management protein fold human biology. Failure can trigger multiple disease states, affecting both health and lifespan. Niemann-Pick C1 (NPC1) is rare genetic disorder triggered by mutations NPC1, multi-spanning transmembrane that trafficked through exocytic pathway to late endosomes (LE) lysosomes (Ly) (LE/Ly) globally manage cholesterol homeostasis. Defects >300 NPC1 variants found...
Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET to separate toxicity is urgently needed. Herein, we report a series furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective inhibitors. representative compound 8l (XY153) potently bound BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value 0.79 nM displayed 354-fold selectivity over BD1....
Abstract Although the impact of genome variation on thermodynamic properties function protein fold has been studied in vitro, it remains a challenge to assign these relationships across entire polypeptide sequence vivo. Using Gaussian process regression based principle Spatial CoVariance, we globally residue-by-residue basis biological that contribute functional CFTR cell. We demonstrate existence thermodynamically sensitive region involving interface between NBD1 and ICL4 contributes its...
Abstract To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing covariance (SCV) relationships that link genetic diversity to fitness individual in response histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants NPC1 gene disrupt cholesterol...
Non-muscle myosin II (NMII) is a force-generating mechanosensitive enzyme that responds to mechanical forces. NMIIs mechanoaccumulate at the cell cortex in response It essential for cells mechanically adapt physical environment, failure of which results mitotic defects when dividing confined environment. Much less known about how NMII mechanoaccumulation regulated during mitosis. We show respond compressive stress by promoting accumulation active RhoA as interphase cells. mechanoresponse...
Genetic variation in human populations can result the misfolding and aggregation of proteins, giving rise to systemic neurodegenerative diseases that require management by proteostasis. Here, we define role GRP94, endoplasmic reticulum Hsp90 chaperone paralog, managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning profile spatial covariance relationships dictate protein folding arising from sequence variants population....
Abstract Urokinase‐type plasminogen activator receptor (uPAR) is a glycosyl phosphatidylinositol‐anchored protein involved in cell adhesion, proliferation, differentiation, migration, invasion, and tissue repair remodeling. Our aim was to investigate uPAR expression the frontal cortex of patients with intractable lobe epilepsy explore possible role epilepsy. Tissue samples were obtained from 25 who had undergone surgery for 15 histologically normal tissues orbital severe contusion (the...
Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed brain and closely related Alzheimer′s disease (AD), its biological functions human become a research focus. In this paper, selenocysteine-coding TGA gene was mutated cysteine-coding TGC used screen fetal cDNA library with yeast two-hybrid system. Our results demonstrated that interacts clusterin (Clu), chaperone...
Eugenol, a plant-derived small compound, shows great medicinal potential. However, whether and how eugenol regulates crop physiology remains elusive. Here we reported that induced Cd (cadmium) tolerance in the root of Brassica rapa. Roots were treated with CdCl2 simultaneously (eugenol + Cd) or pretreated followed by treatment → Cd). Eugenol significantly attenuated Cd-induced growth inhibition, ROS accumulation, oxidative injury, cell death, which confirmed vivo histochemical analysis....