A5060211567- Ubiquitin and proteasome pathways
- Tryptophan and brain disorders
- Peptidase Inhibition and Analysis
- Nuclear Receptors and Signaling
- Protein Degradation and Inhibitors
- Receptor Mechanisms and Signaling
- Organic Chemistry Cycloaddition Reactions
- RNA Research and Splicing
- Macrophage Migration Inhibitory Factor
- Neuropeptides and Animal Physiology
- Genetics and Neurodevelopmental Disorders
- Fungal and yeast genetics research
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Retinoids in leukemia and cellular processes
- Neuroscience and Neuropharmacology Research
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Treatment of Major Depression
- RNA regulation and disease
- Antimicrobial Peptides and Activities
- Cell death mechanisms and regulation
- Signaling Pathways in Disease
- Innovation and Socioeconomic Development
- Neuroethics, Human Enhancement, Biomedical Innovations
Carleton University
2020-2022
Health Canada
2021
McGill University Health Centre
2020
McGill University
2008-2018
Scripps Research Institute
2014-2018
Universidad Nacional Autónoma de México
2005
Abstract A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show allosteric mechanism through which RXR co-operates a permissive partner, peroxisome proliferator-activated (PPAR)-γ, while rendered...
Significance miRNAs are important components of gene regulatory networks and affect all aspects cell biology by controlling the stability translation efficiency their target mRNAs. Here, we identified mRNA cap-binding eIF4E-related protein 4EHP as an effector miRNA-mediated repression. Through screening for interactions in cells via BioID method, a component CCR4–NOT/DDX6/4E-T axis. Direct interaction between 4E-T increases latter’s affinity, suggesting that this potentiates its competition...
Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsaturated fatty acids, including arachidonic acid docosahexaenoic (DHA), interact with the ligand-binding domain (LBD) of a related Nur77/NR4A1. However, binding location whether these other NR4A receptors were not defined. Here, we show acids also Nurr1 LBD, solution NMR spectroscopy reveals epitope DHA at its putative pocket. Biochemical...
Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution the pathophysiology depressive disorders is not fully understood. We investigated involvement MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 2) their target, eIF4E (eukaryotic initiation factor 4E), depression-like behavior mice. Mice carrying mutation for phosphorylation site (Ser209Ala, Eif4e ki/ki), Mnk1/2 double knockout mice (Mnk1/2-/-), or...
Translational control of gene expression plays a key role during the early phases embryonic development. Here we describe transcriptional regulator mouse stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 critical in regulating mESC functions through pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression directs...
Myeloid cell leukemia 1 (MCL-1), an anti-apoptotic BCL-2 family member active in the preservation of mitochondrial integrity during apoptosis, has fundamental roles development and hematopoiesis is dysregulated human cancers. It bears a unique, intrinsically unstructured, N-terminal sequence, which leads to its instability cells hinders protein production structural characterization. Here, we present collective data from NMR spectroscopy titration calorimetry reveal selectivity MCL-1 binding...
Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (<i>Eif4ebp2</i>), encoding suppressor 4E-BP2, leads an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition group I metabotropic glutamate receptors (mGluRs) mGluR1 mGluR5 reverses autistic phenotypes several ASD mouse models. Importantly, these control synaptic...
MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered the cap-binding protein 4EHP is key component mammalian miRNA-Induced Silencing Complex (miRISC), which mediates silencing. However, little known about mRNA repertoire controlled 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify subset mRNAs are translationally 4EHP. show Dusp6...
E3 ubiquitin ligases catalyze the transfer of from an E2-conjugating enzyme to a substrate. UBR5, homologous E6AP C terminus (HECT)-type ligase, mediates ubiquitination proteins involved in translation regulation, DNA damage response, and gluconeogenesis. In addition, UBR5 functions ligase-independent manner by prompting protein/protein interactions without binding partner. Despite recent functional studies, mechanisms substrate recognition selective its partners remain elusive. The harbors...
UBR5 ubiquitin ligase (also known as EDD, Rat100 or hHYD) is a member of the E3 protein family HECT (homologous to E6-AP C-terminus) ligases it contains C-terminal domain. In ubiquitination cascades involving E3s class, transferred from an associated E2 ubiquitin-conjugating enzyme acceptor cysteine domain, which consists structurally distinct N- and C-lobes connected by flexible linker. Here, high-resolution crystal structure C-lobe domain human presented. The reveals important features...
The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively pocket Zn finger named UBR box. Here, we show that box is rigid, but bound water molecules in provide structural plasticity required to bind different positively amino acids. Ultra-high-resolution crystal structures arginine, histidine, and methylated arginine reveal mediate binding N-degron peptides. Using high-throughput assay...
REV-ERBα and REV-ERBβ are members of the nuclear receptor (NR) superfamily ligand-regulated transcription factors that play important roles in regulation circadian physiology, metabolism, immune function. Although REV-ERBs were originally characterized as orphan receptors, recent studies have demonstrated they function receptors for heme. Here, we demonstrate cobalt protoporphyrin IX (CoPP) zinc (ZnPP) ligands bind directly to REV-ERBs. However, instead mimicking agonist action heme, CoPP...
The genome of Saccharomyces cerevisiae is arguably the best studied eukaryotic genome, and yet, it contains approximately 1000 genes that are still relatively uncharacterized. As majority these ORFs have no homologs with characterized sequence or protein structure, traditional sequence-based approaches cannot be applied to deduce their biological function. Here, we characterize YER067W, a conserved gene unknown function strongly induced in response many stress conditions repressed drug...
Abstract Thyrotropin‐releasing hormone is inactivated in the extracellular space by a membrane‐bound peptidase, pyroglutamyl aminopeptidase II (PPII), member of M1 family zinc metallopeptidases. The functional significance multiple PPII RNA species expression unknown. We detected, rat tissues, derived from an alternative processing at exon 14–intron 14 boundary. alternatively processed encoded shorter version (PPII*), lacking part C‐terminal domain. PPII* was expressed COS‐7 (or C6 glioma)...
Nuclear receptor related 1 protein (Nurr1/NR4A2) is an orphan nuclear that considered to function without a canonical ligand-binding pocket. A crystal structure of the Nurr1 domain (LBD) revealed no physical space in conserved region where other receptors with solvent accessible apo-protein pockets bind synthetic and natural ligands. Using solution NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, we show here putative pocket LBD dynamic high...