A5038679338- RNA and protein synthesis mechanisms
- Photoreceptor and optogenetics research
- Receptor Mechanisms and Signaling
- Cellular transport and secretion
- Retinal Development and Disorders
- RNA Research and Splicing
- Cystic Fibrosis Research Advances
- Protein Structure and Dynamics
- Evolution and Genetic Dynamics
- Ultrasound and Hyperthermia Applications
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Bacterial Genetics and Biotechnology
- Respiratory viral infections research
- Energy and Environment Impacts
- Tracheal and airway disorders
- Neonatal Respiratory Health Research
- Viral gastroenteritis research and epidemiology
- Tissue Engineering and Regenerative Medicine
- Neuroscience and Neuropharmacology Research
- Protein Kinase Regulation and GTPase Signaling
- RNA modifications and cancer
- Genomics and Rare Diseases
- Electrospun Nanofibers in Biomedical Applications
Indiana University Bloomington
2018-2025
Indiana University
2023-2024
Pathogenic mutations that cause rhodopsin misfolding lead to a spectrum of currently untreatable blinding diseases collectively termed retinitis pigmentosa. Small molecules correct are therefore urgently needed. In this study, we utilized virtual screening search for drug-like bind the orthosteric site rod opsin and improve its folding trafficking. We identified validated biological effects 2 non-retinoid compounds with favorable pharmacological properties cross blood-retina barrier. These...
Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of cystic transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a common misfolded variant (ΔF508) can be partially rescued therapeutic "correctors" restore its expression. Nevertheless, many other variants are insensitive to correctors. Using deep mutational scanning, we quantitatively compare effects two correctors on plasma membrane 129 variants. Though structural...
Membrane proteins must balance the sequence constraints associated with folding and function against hydrophobicity required for solvation within bilayer. We recently found expression maturation of rhodopsin are limited by its seventh transmembrane domain (TM7), which contains polar residues that essential function. On basis these observations, we hypothesized rhodopsin's should be less tolerant mutations in TM7 relative to those hydrophobic TM domains. To test this hypothesis, used deep...
Cystic Fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Though most people with CF have one or two copies of ΔF508 mutation, there are hundreds other distinct that vary their mechanistic effects and response to therapeutics. Endogenous chaperones known divergent on druggability variants. Nevertheless, it remains unclear how this proteostatic modulation related underlying classes mutations. Here, we survey...
Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most these variants exhibit loss function, molecular defects caused by underlying vary considerably. In this work, we utilize deep mutational scanning quantitatively compare plasma membrane expression 123 known pathogenic presence absence stabilizing cofactor 9-<i>cis</i>-retinal. We identify 69 retinopathy variants,...
Membrane protein variants with diminished conformational stability often exhibit enhanced cellular expression at reduced growth temperatures. The of "temperature-sensitive" is also typically sensitive to corrector molecules that bind and stabilize the native conformation. There are many examples temperature-sensitive rhodopsin variants, misfolding which associated molecular basis retinitis pigmentosa. In this work, we employ deep mutational scanning compare effects temperature 9-cis-retinal,...
The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in molecular basis CF. most common CF variant (ΔF508) remodels both translational regulation and quality control CFTR. Nevertheless, it is unclear how misassembly nascent polypeptide may directly influence activity translation machinery. In this work, we identify structural motif within CFTR transcript that stimulates efficient -1 ribosomal frameshifting...
Abstract The correct expression of folded, functional rhodopsin (Rho) is critical for visual perception. However, this seven-transmembrane helical G protein-coupled receptor prone to mutations with pathological consequences retinal degeneration in retinitis pigmentosa (RP) due Rho misfolding. Pharmacological chaperones that stabilize the inherited variants by assisting their folding and membrane targeting could slow progression RP. In study, we employed virtual screening synthetic compounds...
The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in molecular basis (CF). most common CF variant (ΔF508) remodels both translational regulation and quality control CFTR. Nevertheless, it is unclear how misassembly nascent polypeptide may directly influence activity translation machinery. In this work, we identify structural motif within CFTR transcript that stimulates efficient -1 ribosomal frameshifting...
Abstract Cystic fibrosis (CF) is a chronic genetic disease caused by mutations that compromise the expression and/ or function of cystic transmembrane conductance regulator chloride channel (CFTR). Most people with CF harbor common misfolded CFTR variant (ΔF508), which can be rescued combination therapies containing “corrector” compounds restore its expression. Nevertheless, there are over 400 other variants differ in their sensitivity to correctors for reasons remain unclear. In this work,...
Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability known shape evolution, it unclear how constraints modulate synergistic, epistatic interactions between...
Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability known shape evolution, it unclear how constraints modulate synergistic, epistatic interactions between...
Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability known shape evolution, it unclear how constraints modulate synergistic, epistatic interactions between...
Glycoscience continues to be an underrepresented topic in current undergraduate-biochemistry-laboratory curricula. Of the educational laboratories present this subject area, few introduce students cutting-edge methods and techniques related carbohydrates. A multiweek series of experiments is described that highlights a recently published bleach-mediated-carbohydrate-cleavage protocol context isolation identification soybean glycoprotein, β-conglycinin. Two different levels undergraduate...
Abstract Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most these variants exhibit loss function, molecular defects caused by underlying vary considerably. In this work, we utilize deep mutational scanning quantitatively compare plasma membrane expression 123 known pathogenic presence absence stabilizing cofactor 9- cis -retinal. We identify 69 retinopathy variants,...
Abstract Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability known shape evolution, it unclear how constraints modulate synergistic, epistatic interactions between...
Many eukaryotic membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for mammalian gonadotropin-releasing hormone receptors (GnRHRs), G protein-coupled involved in reproductive steroidogenesis. We recently demonstrated that evolutionary modifications within GnRHRs appear have coincided with adaptive changes cotranslational folding efficiency. Though protein stability known shape interactions, it unclear how...