A5085279555- RNA and protein synthesis mechanisms
- Receptor Mechanisms and Signaling
- Cellular transport and secretion
- Photoreceptor and optogenetics research
- Protein Structure and Dynamics
- RNA Research and Splicing
- RNA modifications and cancer
- Viral Infections and Immunology Research
- Cystic Fibrosis Research Advances
- Bacterial Genetics and Biotechnology
- Retinal Development and Disorders
- Evolution and Genetic Dynamics
- Hypothalamic control of reproductive hormones
- Advanced biosensing and bioanalysis techniques
- Plant Reproductive Biology
- Bacteriophages and microbial interactions
- Lipid Membrane Structure and Behavior
- Respiratory viral infections research
- Mosquito-borne diseases and control
- Genomics and Rare Diseases
- Endoplasmic Reticulum Stress and Disease
- Muscle metabolism and nutrition
- Adipose Tissue and Metabolism
- Insect symbiosis and bacterial influences
- Neonatal Respiratory Health Research
Indiana University Bloomington
2018-2024
Indiana University
2023-2024
Purdue University West Lafayette
2017
Eastern Kentucky University
2005
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...
Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms, including programmed ribosomal frameshifting (PRF), which facilitates the production multiple proteins from single mRNA transcript. PRF is typically stimulated by structural elements within that generate mechanical tension between transcript and ribosome. However, in this work, we show forces generated cotranslational folding nascent polypeptide chain can also enhance PRF. Using an array biochemical,...
Membrane proteins are prone to misfolding and degradation within the cell, yet nature of conformational defects involved in this process remain poorly understood. The earliest stages membrane protein folding mediated by Sec61 translocon, a molecular machine that facilitates lateral partitioning polypeptide into membrane. Proper integration is an essential prerequisite for nascent chain. However, marginal energetic drivers reaction suggest translocon may operate with modest fidelity. In work,...
More than 80 loss-of-function (LOF) mutations in the SLC6A8 creatine transporter (hCRT1) are responsible for cerebral deficiency syndrome (CCDS), which gives rise to a spectrum of neurological defects, including intellectual disability, epilepsy, and autism disorder. To gain insight into nature molecular defects caused by these mutations, we quantitatively profiled cellular processing, trafficking, expression, function eight pathogenic CCDS variants relation wild type (WT) one neutral...
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,...
Abstract Programmed ribosomal frameshifting (PRF) is a translational recoding mechanism that enables the synthesis of multiple polypeptides from single transcript. During translation alphavirus structural polyprotein, efficiency −1PRF coordinated by ‘slippery’ sequence in transcript, an adjacent RNA stem–loop, and conformational transition nascent polypeptide chain. To characterize each these effectors, we measured effects 4530 mutations on deep mutational scanning. While most within...
Membrane proteins are prone to misfolding and degradation. This is particularly true for mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Although they function at plasma membrane, GnRHRs accumulate within secretory pathway. Their apparent instability believed have evolved through selection attenuated GnRHR activity. Nevertheless, molecular basis this adaptation remains unclear. We show that coincides with a C-terminal truncation compromises translocon-mediated...
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...
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 Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms including programmed ribosomal frameshifting (PRF), which facilitates the production multiple proteins from single transcript. PRF is typically stimulated by structural elements within mRNA that generate mechanical tension between transcript and ribosome. However, in this work we show forces generated cotranslational folding nascent polypeptide chain can also enhance PRF. Using an array...
Each step of glycolysis is characterized by a specific enzyme that acts to catalyze given reaction. Unique amongst these reactions the enolase-catalyzed transformation 2-phosphoglycerate into phosphoenolpyruvate dehydration. Studies have shown enolase dimeric structure in all eukaryotes whereas has been observed possess an octameric some extreme thermophile prokaryotes. Though definitive determination molecular architecture not made, anecdotal evidence seems indicate tetrameric association...