Walid A. Houry

Walid A. Houry

Professor

BSc, American University of Beirut, 1990
MSc, Cornell University, 1991
PhD, Cornell University, 1996
Postdoc, Sloan-Kettering Institute, 1997
Postdoc, Max-Planck-Institute for Biochemistry, 2000

Address 661 University Avenue, MaRS Centre
West Tower, Room 1612
Toronto, ON M5G 1M1
Lab Houry Lab
Lab Phone 416-946-7364
Office Phone 416-946-7141
Email walid.houry@utoronto.ca

Editor of the eBook “The Role of AAA+ Proteins in Protein Repair and Degradation” Frontiers Media. doi: 10.3389/978-2-88945-656-7 (2018). Shorter, J. & Houry, W. A. editors.

Board member of the Canadian Society for Molecular Biosciences – councilor (April, 2018 – March, 2020).

Director of the Analytical Ultracentrifugation Facility in the Biochemistry Department, Faculty of Medicine, Medical Science Building, University of Toronto (September, 2004 – current).

Founding member and on the organizing committee of the BiophysTO seminar series, University of Toronto (September, 2015 – current).

Editorial board member of the Journal of Biological Chemistry  (July 1, 2017 – June 30, 2022).

Associate Editor of Frontiers in Protein Folding, Misfolding and Degradation, a section of Frontiers in Molecular Biosciences (January, 2014 – current).

On the Editorial Board of Microbial Cell (January, 2014 – current).

Editor for the Research Topic “The Role of AAA+ Proteins in Protein Repair and Degradation” in Frontiers in Molecular Biosciences (2017).

Editor of the book “Systems Biology & Interactomics: The Molecular Chaperones Interaction Networks in Protein Folding and Degradation”, Springer Science + Business Media (2014).

Editor of The Biomedical & Life Sciences Collection, Henry Stewart Talks Series on “Protein Homeostasis” (2011 – 2012).

Special Editor for the journal Biochemistry and Cell Biology, Special Issue on AAA Proteins (February, 2010).

Editor of The Biomedical & Life Sciences Collection, Henry Stewart Talks Series on “Molecular Chaperones: Principles and Diseases” (2006 – 2007).

Research Lab

I started my group at the University of Toronto in 2000. The ultimate aim of our projects is to address the fundamental question of how molecular chaperones and ATP-dependent proteases modulate protein folding in the cell. To this end, we study the biochemical and biophysical basis of function of these molecular chaperones and proteases as well as their cellular roles in model systems including E. coli, yeast, and mammalian cells. We are also mapping what we call the chaperone interaction networks with the ultimate aim of identifying the rules that govern protein folding processes in the cell. Our group employs a battery of approaches including cell biological, biochemical, biophysical, proteomics, and bioinformatics tools. Our work also has a translational aspect leading to the development of novel antibiotics and anticancers.

Learn more: Houry Lab

Research Description

Cellular Protein Homeostasis Research Group

There are three main projects in my laboratory. One is on the R2TP chaperone complex, the second one is on the Clp system, and the third one is on mapping the chaperone interaction network. The three projects deal with the common theme of cellular stress response. We are also interested in identifying compounds that target protein cellular homeostasis and that can be developed as anticancers or antibacterials.

R2TP

Maintaining protein homeostasis in the cell is mainly accomplished by a family of proteins termed molecular chaperones that assist in protein folding. My group identified a highly conserved protein complex, which we named the R2TP complex, that interacts with several other chaperones and adaptor proteins. R2TP consists of the proteins RUVBL1, RUVBL2, RPAP3, and PIH1D1. R2TP acts as a scaffold for the assembly of other critical complexes in the cell. Hence, R2TP has a novel cellular activity dedicated to protein assembly. The aim of the proposed project is to determine the structure and mechanism of function of this complex using cell biological, biochemical, and structural approaches. We are also interested in identifying compounds that inhibit this complex. Hence, the project sheds further insights into the role of chaperones in general and R2TP in particular in cancer.

Clp system

Our work on the Clp system provided important insights into the function of this chaperone-protease system, especially as regards to its structure and dynamics. Our initial work concentrated on ClpXP from E. coli. ClpX is a hexameric ATP-dependent unfoldase chaperone, while ClpP is a serine protease that forms a cylindrical tetradecamer with narrow axial pores for substrate entry. In the ClpXP complex, ClpX binds target substrates, unfolds them and threads them into ClpP for degradation. We discovered that the mechanism of release of degradation products from the cylindrical protease ClpP is through the formation of transient equatorial side pores that allow for peptide egress. We also discovered compounds that dysregulate ClpP and that have antibacterial activity. Hence, our research in this field sheds novel insights into bacterial infectivity. We are also interested in understanding the function of the ClpXP system in different other organisms including humans.

Mapping chaperone interaction networks

Molecular chaperones are essential components of a quality control machinery present in the cell. They can either aid in the folding and maintenance of newly translated proteins or they can lead to the degradation of misfolded and destabilized proteins. They are also known to be involved in many cellular functions, however, a detailed and comprehensive overview of the interactions between chaperones and their cofactors and substrates is still absent. The heat shock proteins Hsp90, Hsp70/Hsp40, and Hsp60/Hsp10 are typical chaperone systems that are highly conserved across organisms. In this project, we are carrying out systematic mapping of the chaperone interaction networks using a wide range of proteomic and genomic methods. The ultimate goal of the project is to determine the mechanisms that govern protein homeostasis inside the cell.

Awards & Distinctions

2018 — F1000Prime Faculty Member
2015 — Visiting Scientist Award, National Research Foundation of South Africa
2011 — Tokyo Biochemical Research Foundation Award
2001-2006 — Canadian Institutes of Health Research New Investigator
2002-2005 — Premier’s Research Excellence Award
1997-2000 — Fellow of the Max-Planck-Institute
1996-1997 — Fellow of the Howard Hughes Medical Institute

Courses Taught

BCH 2024H Molecular chaperones and cellular protein homeostasis
BCH374Y Research Project in Biochemistry
JBB2026H Protein Structure, Folding and Design
BCH473Y Advanced Research Project in Biochemistry
BCH340H Proteins: from Structure to Proteomics

Publications

View all publications on PubMed

Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death
Wong, K. S., Mabanglo, M. F., Seraphim, T. V., Mollica, A., Mao, Y.-Q., Rizzolo, K., Leung, E., Moutaoufik, M. T., Hoell, L., Phanse, S., Goodreid, J., Barbosa, L. R. S., Ramos, C. H. I., Babu, M., Mennella, V., Batey, R. A., Schimmer A. D., & Houry, W. A.
Cell Chemical Biology 25(8), 1017-1030 (2018)  Read

Systems Analysis of the Genetic Interaction Network of Yeast Molecular Chaperones
Rizzolo, K., Kumar, A., Kakihara, Y., Phanse, S., Minic, Z., Snider, J., Stagljar, I., Zilles, S., Babu, M., & Houry, W. A.
Molecular Omics 14(2), 82–94 (2018)  Read

Features of the Chaperone Cellular Network Revealed through Systematic Interaction Mapping
Rizzolo, K., Huen, J., Kumar, A., Phanse, S., Vlasblom, J., Kakihara, Y., Zeineddine, H. A., Minic, Z., Snider, J., Wang, W., Pons, C., Seraphim, T. V., Boczek, E. E., Alberti, S., Costanzo, M., Myers, C. L., Stagljar, I., Boone, C., Babu, M., & Houry, W. A.
Cell Reports 20(11), 2735–2748 (2017)  Read

The RavA-ViaA Chaperone-Like System Interacts with and Modulates the Activity of the Fumarate Reductase Respiratory Complex
Wong, K. S., Bhandari, V., Janga, S. C., & Houry, W. A.
Journal of Molecular Biology 429(2), 324–344 (2017)  Read

Mechanism of Amyloidogenesis of a Bacterial AAA+ Chaperone
10. Chan, S. W. S., Yau, J., Ing, C., Liu, K., Farber, P., Won, A., Bhandari, V., Kara-Yacoubian, N., Seraphim, T. V., Chakrabarti, N., Kay, L. E., Yip, C. M., Pomès, R., Sharpe, S., & Houry, W. A.
Structure 24(7), 1095–1109 (2016)  Read