Spike Protein

RNA Polymerase

Structure of SARS-CoV-2

Coronavirus

Protease

Benoit Coulombe, PhD

Director, Department of Translational Proteomics, IRCM

Bell-Bombardier Research Chair, IRCM

Professor, Department of Biochemistry & Molecular Medicine, U of Montréal

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The fight against this coronavirus has only just begun

 

OVERALL GOAL

Our lab recently redirected its main focus and is now harnessing the power of proteomics, biochemistry and chemical biology to decipher and ultimately inhibit the mechanisms underlying replication of SARS-COV-2, the coronavirus that causes COVID-19 and a range of collateral damage that remains to be fully defined.

We closely follow the evolution of other animal viruses that already replicate in humans but do not yet transmit from human to human. Other projects are also underway in our laboratory.

Our group adopts a resolutely innovative modus operandi, which contributes to shaking up our classic methods by creating a transdisciplinary and open ecosystem where totally distinct approaches collide to allow both the study of the atomic structure of proteins and their organization in complex networks, both the analysis of microscopic model systems and of patient cohorts, both the screening of small molecules and their development to create affordable drugs.

To join our group as a graduate student or a postdoctoral fellow, please send a motivation letter and a complete CV by email directly to Benoit.Coulombe@ircm.qc.ca. Only candidates of interest will be contacted.

FUNCTION AND REGULATION OF THE SPIKE SURFACE PROTEIN

The S gene encodes a surface glycoprotein named Spike that plays a central role in targeting and invading host cells. We use a powerful method called Phage Display to discover peptides/proteins that can bind Spike with high affinity. These binders are used to develop inhibitors of viral entry and sensitive detection tools to monitor the virus in biological samples.

FUNCTION AND REGULATION OF THE COVID-19 RNA-SYNTHESIZING MACHINE

The nsp12 gene encodes an RNA-dependent RNA Polymerase that copies the viral genome not only to generate RNA molecules that can be translated into proteins, but also numerous copies of the genome for biogenesis of new viral particles. Mutations produced through genome copying by the RNA polymerase can eventually generate new functions that modify the properties of the virus and eventually increase its virulence. The nsp12 protein is a target for drug discovery and the FDA/Health Canada-approved drug Remdesivir is a nucleotide analogue that inhibits viral RNA polymerase function. We study the function of nsp12 and its regulation mechanisms to better understand how to efficiently inhibit this protein and thereby viral replication. Interactions of the RNA polymerase machinery (nsp12 works in concert with nsp7, 8, 9, 10 and 14) with host factors are also scrutinized to discover new regulatory mechanisms.

COMPUTATIONAL VALIDATION OF THE SARS-COV-2 PROTEIN INTERACTOME

Computational analysis of protein-protein interaction datasets is essential to build high-confidence networks. We develop and apply bioinformatic tools for the analysis of viral-host protein interactions.

10 MOST SIGNIFICANT DISCOVERIES FROM OUR LAB

1998: The Promoter DNA Wrapping Model

Robert F, Douziech M, Forget D, Egly JM, Greenblatt J, Burton ZF, Coulombe B.

Wrapping of promoter DNA around the RNA polymerase II initiation complex induced by TFIIF.

Mol Cell. 1998 Sep;2(3):341-51.

2007: The RNA polymerase II interactome and RNA Polymerase II-Associated Proteins (RPAPs)

Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Thérien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, Hughes TR, Blanchette M, Price DH, Coulombe B.

Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.

Mol Cell. 2007 Jul 20;27(2):262-74.

2013: A Novel Family of Lysine Methyltransferases That Target Molecular Chaperones

Cloutier P, Lavallée-Adam M, Faubert D, Blanchette M, Coulombe B.

A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.

PLoS Genet. 2013;9(1):e1003210.

2015: Leukodystrophy-Causing Mutations Impair RNA polymerase III Biogenesis

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, Coulombe B, Bernard G.

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Nat Commun. 2015 Jul 7;6:7623.

2017: The R2TP/PFD-like Complex Regulates Assembly of the U5 snRNP and TSC complex

Cloutier P, Poitras C, Durand M, Hekmat O, Fiola-Masson É, Bouchard A, Faubert D, Chabot B, Coulombe B.

R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.

Nat Commun. 2017 May 31;8:15615.

2018: The Particle for Arrangement of Quaternary structure (PAQosome)

Houry WA, Bertrand E, Coulombe B.

The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation.

Trends Biochem Sci. 2018 Jan;43(1):4-9.

2018: A Model for Interactome Wiring by the PAQosome

Coulombe B, Cloutier P, Gauthier MS.

How do our cells build their protein interactome?

Nat Commun. 2018 Jul 27;9(1):2955.

2018: Phosphorylated PCSK9 Is a Potent Biomarker for Various Diseases

Gauthier MS, Awan Z, Bouchard A, Champagne J, Tessier S, Faubert D, Chabot K, Garneau PY, Rabasa-Lhoret R, Seidah NG, Ridker PM, Genest J, Coulombe B.

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics.

J Clin Lipidol. 2018 Jul-Aug;12(4):1027-1038.

2018: Mutations in the Glutamyl-Prolyl-tRNA Synthetase Gene Cause a Hypomyelinating Leukodystrophy

Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G.

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.

Am J Hum Genet. 2018 Apr 5;102(4):676-684.

2020: Complete Subunit Composition of the PAQosome

Cloutier P, Poitras C, Faubert D, Bouchard A, Blanchette M, Gauthier MS, Coulombe B.

Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome.

J Proteome Res. 2020 Jan 3;19(1):18-27.

 
 

TEAM

Dr. Benoit Coulombe
Dr. Benoit Coulombe
Director
Dr. Marie-Soleil Gauthier
Dr. Marie-Soleil Gauthier
Senior Associate Researcher
maxime_pinard_small.png
Dr. Maxime Pinard
Associate Researcher
esen_sokullu.png
Dr. Esen Sokullu
Postdoctoral Fellow
Christian Poitras
Christian Poitras
Systems Analyst
Alexa Derksen
Alexa Derksen
Master Degree Student (Dr. G. Bernard)
Golden Marble
Vijaya Madhoo
Administrative Assistant
Diane Forget
Diane Forget
Honorary Lab Member

2020-06-26 :

Diane Forget prend sa retraite après 27 ans de service dévoué pour le laboratoire. Elle a eu

une contribution exceptionnelle pour nos publications, la formation de personnel, l'administration des fonds de recherche et la planification des espaces de laboratoire. Avec toute notre reconnaissance, merci et bonne continuation.

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