11 results on '"Sylvain Lanouette"'
Search Results
2. Improvements in cough severity and cough-related quality of life in a phase 2 trial (RELIEF) with the P2X3 antagonist BLU-5937 in refractory chronic cough (RCC)
- Author
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Laurent Harvey, Mandel Sher, James H. Hull, Sylvain Lanouette, Surinder S. Birring, Catherine M. Bonuccelli, Alyn H. Morice, Alan B. Goldsobel, Jaclyn A. Smith, and Ella Li
- Subjects
medicine.medical_specialty ,Chronic cough ,Refractory ,Quality of life ,business.industry ,Internal medicine ,Antagonist ,Medicine ,medicine.symptom ,business - Published
- 2021
3. Discovery of Substrates for a SET Domain Lysine Methyltransferase Predicted by Multistate Computational Protein Design
- Author
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Sylvain Lanouette, James A. Davey, Fred Elisma, Daniel Figeys, Zhibin Ning, Roberto A. Chica, and Jean-François Couture
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Models, Molecular ,Methyltransferase ,Protein design ,Lysine ,Peptide ,Biology ,Protein Engineering ,Proteomics ,Substrate Specificity ,Protein structure ,Structural Biology ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Protein Interaction Maps ,Molecular Biology ,Peptide sequence ,chemistry.chemical_classification ,Computational Biology ,Histone-Lysine N-Methyltransferase ,Methylation ,Protein Structure, Tertiary ,HEK293 Cells ,Biochemistry ,chemistry ,Mutagenesis, Site-Directed - Abstract
SummaryCharacterization of lysine methylation has proven challenging despite its importance in biological processes such as gene transcription, protein turnover, and cytoskeletal organization. In contrast to other key posttranslational modifications, current proteomics techniques have thus far shown limited success at characterizing methyl-lysine residues across the cellular landscape. To complement current biochemical characterization methods, we developed a multistate computational protein design procedure to probe the substrate specificity of the protein lysine methyltransferase SMYD2. Modeling of substrate-bound SMYD2 identified residues important for substrate recognition and predicted amino acids necessary for methylation. Peptide- and protein- based substrate libraries confirmed that SMYD2 activity is dictated by the motif [LFM]−1-K∗-[AFYMSHRK]+1-[LYK]+2 around the target lysine K∗. Comprehensive motif-based searches and mutational analysis further established four additional substrates of SMYD2. Our methodology paves the way to systematically predict and validate posttranslational modification sites while simultaneously pairing them with their associated enzymes.
- Published
- 2015
4. A charge-suppressing strategy for probing protein methylation
- Author
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Daniel Figeys, Sylvain Lanouette, Jean-François Couture, Janice Mayne, Zhibin Ning, Anna S. Mierzwa, and Alexandra Therese Star
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0301 basic medicine ,Arginine ,Lysine ,Ion chromatography ,Peptide ,Methylation ,Catalysis ,Mass Spectrometry ,03 medical and health sciences ,Materials Chemistry ,Protein methylation ,Epigenetics ,Amino Acid Sequence ,Regulation of gene expression ,chemistry.chemical_classification ,Metals and Alloys ,Proteins ,General Chemistry ,Chromatography, Ion Exchange ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,030104 developmental biology ,Biochemistry ,chemistry ,Ceramics and Composites ,Peptides - Abstract
Methylation of arginine and lysine (RK) residues play essential roles in epigenetics and the regulation of gene expression. However, research in this area is often hindered by the lack of effective tools for probing the protein methylation. Here, we present an antibody-free strategy to capture protein methylation on RK residues by using chemical reactions to eliminate the charges on un-modified RK residues and peptide N-termini. Peptides containing methylated RK residues remain positively charged and are then enriched by strong cation exchange chromatography, followed by high-resolution mass spectrometry identification.
- Published
- 2016
5. List of Contributors
- Author
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Kim Barroso, Olivier Binda, Maria Victoria Botuyan, Anna L. Chambers, Eric Chevet, Jocelyn Côté, Florence Couteau, Jean-François Couture, Jessica A. Downs, Joel C. Eissenberg, Maite G. Fernandez-Barrena, Martin Ernesto Fernandez-Zapico, Raquel Fueyo, María Alejandra García, Alexandre Gaspar-Maia, John Haddad, Nasim Haghandish, Elisabeth Hessmann, Jonathan M.G. Higgins, Ryan A. Hlady, Timothy C. Humphrey, Steven A. Johnsen, Alexander Koenig, María Julia Lamberti, Sylvain Lanouette, Andrew Liss, Gwen A. Lomberk, Frédérick A. Mallette, Sridhar Mani, Marian A. Martínez-Balbás, Georges Mer, Emma A. Morrison, Catherine A. Musselman, Sankari Nagarajan, Christopher L. Pin, Keith D. Robertson, Andrea Ropolo, María Roqué, Natalia Belén Rumie Vittar, Güenter Schneider, Ana Sevilla, Steven G. Smith, Maria Carolina Touz, Raul Urrutia, Laura Vargas-Roig, Renzo Emanuel Vera, Nikolaus A. Watson, Xiang-Jiao Yang, Pamela Zhang, and Ming-Ming Zhou
- Published
- 2016
6. Impacts of Histone Lysine Methylation on Chromatin
- Author
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Jean-François Couture, Sylvain Lanouette, Pamela Zhang, and J. Haddad
- Subjects
Histone H4 ,Genetics ,Histone H3 ,Histone lysine methylation ,Histone methyltransferase ,Histone H2A ,Histone methylation ,Histone code ,Cancer epigenetics ,Biology - Abstract
Since its initial discovery by Allfrey and colleagues, methylation of histone proteins on lysine residues has emerged as an important posttranslational modification controlling a myriad of nuclear events, such as DNA damage repair, transcription, and replication. Following the biochemical characterization of the first histone K methyltransferase in 2000, efforts have uncovered the mechanistic basis underlying the activity of several histone lysine methyltransferases (HKMTs) and the impact of the reactions they catalyzed. Moreover, high-throughput sequencing and genome-wide association studies demonstrated that histone methyltransferases are linked to aggressive forms of cancers, including, but not limited to, lymphomas, leukemias, and gliomas, thereby opening new avenues for therapeutic interventions. In this chapter, we focus on histone H3 Lys-4, Lys-9, Lys-27, Lys-36, and Lys-79, as well as histone H4 Lys-20 methyltransferases.
- Published
- 2016
7. Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2
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Daniel Figeys, Jean-François Couture, Véronique Tremblay, Fred Elisma, Jeffery Butson, Sylvain Lanouette, and Mohamed Abu-Farha
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Regulation of gene expression ,Genetics ,Methyltransferase ,Cell Biology ,General Medicine ,Computational biology ,Methylation ,Biology ,Methylation Site ,Protein structure ,Histone ,Histone methyltransferase ,Proteome ,biology.protein ,Molecular Biology - Abstract
The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. Initially identified as genuine histone methyltransferases, specific members of this family have recently been shown to methylate non-histone proteins such as p53, VEGFR, and the retinoblastoma tumor suppressor (pRb). To gain further functional insights into this family of KMTs, we generated the protein interaction network for three different human SMYD proteins (SMYD2, SMYD3, and SMYD5). Characterization of each SMYD protein network revealed that they associate with both shared and unique sets of proteins. Among those, we found that HSP90 and several of its co-chaperones interact specifically with the tetratrico peptide repeat (TPR)-containing SMYD2 and SMYD3. Moreover, using proteomic and biochemical techniques, we provide evidence that SMYD2 methylates K209 and K615 on HSP90 nucleotide-binding and dimerization domains, respectively. In addition, we found that each methylation site displays unique reactivity in regard to the presence of HSP90 co-chaperones, pH, and demethylation by the lysine amine oxidase LSD1, suggesting that alternative mechanisms control HSP90 methylation by SMYD2. Altogether, this study highlights the ability of SMYD proteins to form unique protein complexes that may underlie their various biological functions and the SMYD2-mediated methylation of the key molecular chaperone HSP90.
- Published
- 2011
8. Structural and Biochemical Insights into MLL1 Core Complex Assembly
- Author
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Jean-François Couture, Sylvain Lanouette, Adam F. Groulx, Pamela Zhang, Joseph S. Brunzelle, Véronique Tremblay, and Vanja Avdic
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Methyltransferase ,Stereochemistry ,Recombinant Fusion Proteins ,Amino Acid Motifs ,Molecular Sequence Data ,Sequence alignment ,Plasma protein binding ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Protein structure ,Structural Biology ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Protein Structure, Quaternary ,Ternary complex ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Methylation ,Histone-Lysine N-Methyltransferase ,3. Good health ,Protein Structure, Tertiary ,DNA-Binding Proteins ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,Protein Multimerization ,Sequence Alignment ,Myeloid-Lymphoid Leukemia Protein ,Protein Binding - Abstract
SummaryHistone H3 Lys-4 methylation is predominantly catalyzed by a family of methyltransferases whose enzymatic activity depends on their interaction with a three-subunit complex composed of WDR5, RbBP5, and Ash2L. Here, we report that a segment of 50 residues of RbBP5 bridges the Ash2L C-terminal domain to WDR5. The crystal structure of WDR5 in ternary complex with RbBP5 and MLL1 reveals that both proteins binds peptide-binding clefts located on opposite sides of WDR5′s β-propeller domain. RbBP5 engages in several hydrogen bonds and van der Waals contacts within a V-shaped cleft formed by the junction of two blades on WDR5. Mutational analyses of both the WDR5 V-shaped cleft and RbBP5 residues reveal that the interactions between RbBP5 and WDR5 are important for the stimulation of MLL1 methyltransferase activity. Overall, this study provides the structural basis underlying the formation of the WDR5-RbBP5 subcomplex and further highlight the crucial role of WDR5 in scaffolding the MLL1 core complex.
- Published
- 2011
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9. Fine‐tuning the stimulation of MLL1 methyltransferase activity by a histone H3‐based peptide mimetic
- Author
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Sylvain Lanouette, Vanja Avdic, Pamela Zhang, Anastassia Voronova, Jean-François Couture, and Ilona S. Skerjanc
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Epigenomics ,Methyltransferase ,Biology ,Biochemistry ,Histones ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Histone H1 ,Peptide Library ,Histone H2A ,Histone methylation ,Genetics ,Humans ,Histone octamer ,Molecular Biology ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Crystallography ,Stem Cells ,Molecular Mimicry ,EZH2 ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Acetylation ,Cell Differentiation ,Histone-Lysine N-Methyltransferase ,DNA Methylation ,Nucleosomes ,Protein Structure, Tertiary ,DNA-Binding Proteins ,Models, Chemical ,030220 oncology & carcinogenesis ,Histone methyltransferase ,Myeloid-Lymphoid Leukemia Protein ,Protein Binding ,Transcription Factors ,Biotechnology - Abstract
The SET1 family of methyltransferases carries out the bulk of histone H3 Lys-4 methylation in vivo. One of the common features of this family is the regulation of their methyltransferase activity by a tripartite complex composed of WDR5, RbBP5, and Ash2L. To selectively probe the role of the SET1 family of methyltransferases, we have developed a library of histone H3 peptide mimetics and report herein the characterization of an Nα acetylated form of histone H3 peptide (NαH3). Binding and inhibition studies reveal that the addition of an acetyl moiety to the N terminus of histone H3 significantly enhances its binding to WDR5 and prevents the stimulation of MLL1 methyltransferase activity by the WDR5-RbBP5-Ash2L complex. The crystal structure of NαH3 in complex with WDR5 reveals that a high-affinity hydrophobic pocket accommodates the binding of the acetyl moiety. These results provide the structural basis to control WDR5-RbBP5-Ash2L-MLL1 activity and a tool to manipulate stem cell differentiation programs.
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- 2010
10. Crystal structure of the trithorax group protein Ash2L reveals a Forkhead-like DNA binding domain
- Author
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Sylvain Lanouette, Pamela Zhang, Vanja Avdic, Marjorie Brand, Sabina Sarvan, Véronique Tremblay, Alexandre Blais, Joseph S. Brunzelle, Chandra Prakash Chaturvedi, and Jean-François Couture
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Models, Molecular ,Histone H3 Lysine 4 ,Methyltransferase ,animal structures ,HMG-box ,Amino Acid Motifs ,Crystallography, X-Ray ,Article ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Structural Biology ,Humans ,Molecular Biology ,Locus control region ,030304 developmental biology ,0303 health sciences ,biology ,Nuclear Proteins ,DNA-binding domain ,DNA ,Molecular biology ,Cell biology ,Protein Structure, Tertiary ,DNA-Binding Proteins ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,Binding domain ,Transcription Factors - Abstract
Ash2L is part of a complex involved in histone H3 lysine 4 trimethylation, linked to active transcription. Ash2L is now found to contain a helix-wing-helix DNA binding domain that is needed for targeting and H3K4 trimethylation at the β-globin locus control region in vivo. Absent, small or homeotic discs–like 2 (ASH2L) is a trithorax group (TrxG) protein and a regulatory subunit of the SET1 family of lysine methyltransferases. Here we report that ASH2L binds DNA using a forkhead-like helix-wing-helix (HWH) domain. In vivo, the ASH2L HWH domain is required for binding to the β-globin locus control region, histone H3 Lys4 (H3K4) trimethylation and maximal expression of the β-globin gene (Hbb-1), validating the functional importance of the ASH2L DNA binding domain.
- Published
- 2011
11. The functional diversity of protein lysine methylation
- Author
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Vanessa Mongeon, Daniel Figeys, Sylvain Lanouette, and Jean-François Couture
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lysine demethylation ,Lysine ,Embo17 ,Review ,Proteomics ,Methylation ,complex mixtures ,General Biochemistry, Genetics and Molecular Biology ,Histones ,proteomics ,Ubiquitin ,Amino Acid Sequence ,General Immunology and Microbiology ,biology ,Systems Biology ,Applied Mathematics ,EZH2 ,Ubiquitination ,Proteins ,Acetylation ,lysine methylation ,Histone ,Computational Theory and Mathematics ,Biochemistry ,networks ,Histone methyltransferase ,biology.protein ,bacteria ,General Agricultural and Biological Sciences ,Protein Processing, Post-Translational ,Embo31 ,Information Systems - Abstract
Large‐scale characterization of post‐translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, has highlighted their importance in the regulation of a myriad of signaling events. While high‐throughput technologies have tremendously helped cataloguing the proteins modified by these PTMs, the identification of lysine‐methylated proteins, a PTM involving the transfer of one, two or three methyl groups to the ε‐amine of a lysine side chain, has lagged behind. While the initial findings were focused on the methylation of histone proteins, several studies have recently identified novel non‐histone lysine‐methylated proteins. This review provides a compilation of all lysine methylation sites reported to date. We also present key examples showing the impact of lysine methylation and discuss the circuitries wired by this important PTM.
- Published
- 2014
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