A5038098410- Evolution and Genetic Dynamics
- Genomics and Phylogenetic Studies
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Microtubule and mitosis dynamics
- Cystic Fibrosis Research Advances
- Evolutionary Game Theory and Cooperation
- Bioinformatics and Genomic Networks
- Cytokine Signaling Pathways and Interactions
- CRISPR and Genetic Engineering
- interferon and immune responses
- Bacterial Genetics and Biotechnology
- Gut microbiota and health
- Microbial Metabolic Engineering and Bioproduction
- RNA regulation and disease
- RNA modifications and cancer
- Bacteriophages and microbial interactions
- Advanced biosensing and bioanalysis techniques
- Genetic diversity and population structure
- Legume Nitrogen Fixing Symbiosis
- Viral gastroenteritis research and epidemiology
- Antibiotic Resistance in Bacteria
- Neuropeptides and Animal Physiology
- Ion channel regulation and function
- Pharmacological Receptor Mechanisms and Effects
Université de Montréal
2016-2024
Harvard University
2011-2018
University of North Carolina at Chapel Hill
2006-2011
Institute of Molecular Biology and Biophysics
2008
Astronomy and Space
2008
Vetenskap I Skolan
2008
Rivers Hospital
2008
Deletion of phenylalanine-508 (Phe-508) from the N-terminal nucleotide-binding domain (NBD1) cystic fibrosis transmembrane conductance regulator (CFTR), a member ATP-binding cassette (ABC) transporter family, disrupts both its folding and function causes most fibrosis. Most mutant nascent chains do not pass quality control in ER, those that remain thermally unstable, only partially functional, are rapidly endocytosed degraded. Although lack Phe-508 peptide backbone diminishes NBD1 yield,...
What are the molecular properties of proteins that fall on radar protein quality control (PQC)? Here we mutate E. coli's gene encoding dihydrofolate reductase (DHFR) and replace it with bacterial orthologous genes to determine how components PQC modulate fitness effects these genetic changes. We find chaperonins GroEL/ES protease Lon compete for binding molten globule intermediate DHFR, resulting in a peculiar symmetry their action: overexpression deletion both restore growth deleterious...
The consistent observation across all kingdoms of life that highly abundant proteins evolve slowly demonstrates cellular abundance is a key determinant protein evolutionary rate. However, other empirical findings, such as the broad distribution rates, suggest additional variables determine rate evolution. Here, we report under global selection against cytotoxic effects misfolded proteins, folding stability (ΔG), simultaneous with abundance, causal variable Using both theoretical analysis and...
Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of foreign genes are poorly understood. Here we performed inter-species replacement chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous replacements caused marked drop (in range 10–90%) growth rate despite fact that most DHFRs as stable E.coli...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) ion channel mutated in patients with fibrosis. most common mutation, deletion of phenylalanine 508 (DeltaF508) and many other disease-associated mutations occur the nucleotide binding domains (NBD) cytoplasmic loops (CL) membrane-spanning (MSD). A recently constructed computational model CFTR three-dimensional structure, supported by experimental data (Serohijos, A. W., Hegedus, T.,...
The patterns of polymorphisms in genomes are imprints the evolutionary forces at play nature. In particular, have been extensively used to infer fitness effects mutations and their dynamics fixation. However, role contribution molecular biophysics these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, selection against cytotoxic misfolding, explicit population simulations polyclonal regime. First, recapitulate results on clonal...
Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as ∼10–20 fold increase in myoglobin (Mb) concentration skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity Mbs is not significantly different among mammals (with typical oxygenation constants ∼0.8–1.2 µM−1), folding stabilities cetacean are ∼2–4 kcal/mol higher than Mbs. Using ancestral sequence reconstruction,...
Viral evolutionary pathways are determined by the fitness landscape, which maps viral genotype to fitness. However, a quantitative description of landscape and forces on it remain elusive. Here, we apply biophysical model based capsid folding stability antibody binding affinity predict pathway norovirus escaping neutralizing antibody. The is validated experimental evolution in bulk culture drop-based microfluidics that propagates millions independent small subpopulations. We demonstrate...
Understanding the relative contributions of various evolutionary processes-purifying selection, neutral drift, and adaptation-is fundamental to biology. A common metric distinguish these processes is ratio nonsynonymous synonymous substitutions (i.e., dN/dS) interpreted from theory as a null model. However, biophysical considerations, mutations have non-negligible effects on properties proteins such folding stability. In this work, we investigated how stability affects rate protein evolution...
Chromatin compaction defines genome topology, evolution, and function. The Saccharomycotina subphylum, including the fermenting yeast Saccharomyces cerevisiae have a decompacted genome, possibly because they lost two genes mediating specific histone lysine methylation binding protein heterochromatin 1 (HP1). This decompaction may result in higher-than-expected mutation meiotic recombination rates observed this species. To test hypothesis, we retro-engineered S. to compact by expressing HP1...
Comprehensive and systematic proteome-wide experiments require financial technical resources unavailable to most researchers. Here we describe a scalable CRISPR/Cas9-non-homologous end joining (NHEJ) based method for Pooled Recombinant Integration of Seamless Markers (PRISM) into protein coding genes. We created two gRNA libraries 5'- 3'-tagging 18,804 human protein-coding Selection in-frame integration the donor cassette can be guaranteed by fusing it an antibiotic resistance enzyme (ARE)...
Cysteine-rich intestinal protein 1 (CRIP1) has been identified as a novel marker for early detection of cancers. Here we report on the use phage display in combination with molecular modeling to identify high-affinity ligand CRIP1. Panning experiments using circularized C7C library yielded several consensus sequences modest binding affinities purified Two sequence motifs, A1 and B5, having highest CRIP1, were chosen further study. With peptide structure information NMR higher-affinity was...
The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes epithelial cells is responsible for cystic fibrosis (CF). Over 90% CF patients carry at least one mutant allele with deletion phenylalanine position 508 located in N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that ΔF508 exhibits inefficient biosynthetic maturation susceptibility to degradation...
The emergence of a novel A(H1N1) strain in 2009 was the first influenza pandemic genomic age, and unprecedented surveillance virus provides opportunity to better understand evolution influenza. We examined changes nucleotide coding regions amino acid sequences hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP) segments A(H1N1)pdm09 using publicly available data. calculated hamming distance from vaccine A/California/07/2009 for each sequence. also estimated Pepitope–a measure...
Protein thermodynamics are an integral determinant of viral fitness and one the major drivers protein evolution. Mutations in influenza A virus (IAV) hemagglutinin (HA) can eliminate neutralizing antibody binding to mediate escape from preexisting antiviral immunity. Prior research on IAV nucleoprotein suggests that stability may constrain seasonal evolution; however, role shaping evolutionary dynamics HA has not been explored. We used full coding sequence 9,797 H1N1pdm09 sequences 16,716...
ABSTRACT Human noroviruses (HuNoVs) are positive-sense RNA viruses that can cause severe, highly infectious gastroenteritis. HuNoV outbreaks frequently associated with recombination between circulating strains. Strain genotyping and phylogenetic analyses show often recombine in a conserved region near the junction of viral polyprotein (open reading frame 1 [ORF1]) capsid (ORF2) genes occasionally within RNA-dependent polymerase (RdRP) gene. Although methods useful for tracking changes...
Intracellular active transport is driven by ATP-hydrolyzing motor proteins that move along cytoskeletal filaments. In particular, the microtubule-associated dynein involved in of organelles and vesicles, maintenance Golgi, mitosis. However, unlike kinesin myosin, mechanism which converts chemical energy into mechanical force remains largely a mystery, due primarily to lack high-resolution molecular structure. Using homology modeling normal mode analysis, we propose complete atomic structure...