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 1 King's College Circle
Medical Sciences Building, Room 5308
Toronto, ON M5S 1A8
Lab Houry Lab
Lab Phone 416-946-7364
Office Phone 416-946-7141
Email walid.houry@utoronto.ca

Director and principal applicant for the CIHR training program grant in “Protein Folding and Interaction Dynamics: Principles and Diseases” at the Department of Biochemistry, University of Toronto (June, 2002 – current).

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

Co-chair of the Basic Sciences panel of the Faculty of Medicine Research Grants Committee (Dean’s fund) at the University of Toronto (November, 2012 – current)

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 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

The Function of Molecular Chaperones and ATP-dependent Proteases in Protein Homeostasis

In their natural habitats, enterobacteria are constantly under assault by a wide array of environmental stresses. One of the most frequently encountered hostile conditions is acid stress. Neutralophiles like Escherichia coli must travel through the host’s digestive tract, which includes the stomach and intestine, before reaching the bowel where pathogenesis typically occurs. In the stomach, bacteria must endure a pH of about 2 with an emptying time of approximately two hours before reaching the less acidic environment of the intestinal tract (pH 4-5). An organism’s ability to withstand acid stress has been directly correlated with its infectious dose. Therefore, bacteria have evolved very complex acid stress response systems. Our understanding of the genetic, biochemical, and biophysical properties of these systems is still very rudimentary. We are studying the mechanisms by which molecular chaperones and enzyme decarboxylases help to maintain protein homeostasis under such conditions.

Specific systems that we are currently concentrating on include the ClpXP chaperone-protease system, the RavA/ViaA chaperone system, and the lysine decarboxylase acid stress response enzyme. Furthermore, our work on the ClpXP system has led to the development of a novel class of antibiotics that we term activators of self-compartmentalizing proteases, ACPs. Hence, our research in this field sheds novel insights into bacterial infectivity.

The role of molecular chaperones and enzyme decarboxylases in the acid stress response of E. coli

In their natural habitats, enterobacteria are constantly under assault by a wide array of environmental stresses. One of the most frequently encountered hostile conditions is acid stress. Neutralophiles like Escherichia coli must travel through the host’s digestive tract, which includes the stomach and intestine, before reaching the bowel where pathogenesis typically occurs. In the stomach, bacteria must endure a pH of about 2 with an emptying time of approximately two hours before reaching the less acidic environment of the intestinal tract (pH 4-5). An organism’s ability to withstand acid stress has been directly correlated with its infectious dose. Therefore, bacteria have evolved very complex acid stress response systems. Our understanding of the genetic, biochemical, and biophysical properties of these systems is still very rudimentary. We are studying the mechanisms by which molecular chaperones and enzyme decarboxylases help to maintain protein homeostasis under such conditions.

Specific systems that we are currently concentrating on include the ClpXP chaperone-protease system, the RavA/ViaA chaperone system, and the lysine decarboxylase acid stress response enzyme. Furthermore, our work on the ClpXP system has led to the development of a novel class of antibiotics that we term activators of self-compartmentalizing proteases, ACPs. Hence, our research in this field sheds novel insights into bacterial infectivity.

Analysis of Hsp90 and the R2TP complex cellular functions

Eukaryotic Hsp90 is a ubiquitous molecular chaperone that plays a central role in cellular signaling since it is essential for maintaining the activity of several signaling proteins including steroid hormone receptors and protein kinases. Hsp90 is found to be overexpressed in cancer cells; as a result, Hsp90 is currently a novel anti-cancer drug target. The chaperone typically functions as part of large complexes, which include other chaperones and essential cofactors that regulate Hsp90 activity. It is thought that different cofactors target Hsp90 to different sets of substrates. However, the mechanism of Hsp90 function remains poorly understood. As part of an effort aimed at elucidating the cellular functions of Hsp90, we had identified two highly conserved novel Hsp90 interactors, termed Tah1 and Pih1 (also called Nop17). Tah1 and Pih1 bind to the chaperone and also associate physically and functionally with the essential AAA+-type helicases Rvb1 and Rvb2 to form what we call the R2TP complex (Rvb1-Rvb2-Tah1-Pih1). The helicases are critical components of several key multiprotein complexes including the chromatin remodeling complexes INO80 and SWR-C, the Tip60 histone acetyltransferase complex, and the telomerase complex. Rvb1 and Rvb2 are also found to be involved in snoRNA maturation and pre-rRNA processing. The R2TP complex is conserved from yeast to humans.

Our recent efforts aimed at analyzing the effect of Tah1 and Pih1 on Hsp90 activity using yeast as model system. This led us to a very surprising finding that suggested a novel role of the chaperone in pre-rRNA processing. We found that Hsp90 and R2TP are involved in the biogenesis of box C/D small nucleolar RNA-protein (snoRNP) complexes that are required for the processing of pre-ribosomal RNA. Our working model is that Hsp90 and R2TP complex function to promote the proper biogenesis of snoRNA-protein complexes, which are subsequently important for pre-rRNA processing and maturation. Our efforts on this project are aimed at elucidating at the molecular level the ultimate effect of Hsp90 and R2TP on ribosome biogenesis. This project sheds further insights into the role of Hsp90, Rvb1, and Rvb2 in cancer.

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

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

BCH374Y Research Project in Biochemistry
JBB2026H Protein Structure, Folding and Design
BCH473Y Advanced Research Project in Biochemistry
BCH340H Proteins: from Structure to Proteomics

Extra-Departmental Courses

CHMB62H3 Introduction to Biochemistry

Publications

View all publications on PubMed

Nutritional Status Modulates Box C/D snoRNP Biogenesis by Regulated Subcellular Relocalization of the R2TP Complex
Kakihara, Y., Makhnevych, T., Zhao, L., Tang, W., & Houry, W. A.
Genome Biology 15(7): 404, 1-20 (2014)  Read

Structural Insights into the Inactive Subunit of the Apicoplast-Localized Caseinolytic Protease Complex of Plasmodium falciparum
El Bakkouri, M., Rathore, S., Calmettes, C., Wernimont, A. K., Liu, K., Sinha, D., Asad, M., Jung, P., Hui, R., Mohmmed, A., & Houry, W. A.
The Journal of Biological Chemistry 288(2), 1022-1031 (2013)  Read

Hsp110 is Required for Spindle Length Control
Makhnevych, T., Wong, P., Pogoutse, O., Vizeacoumar, F. J., Greenblatt, J. F., Emili, A., & Houry, W. A.
Journal of Cell Biology 198(4), 623-636 (2012)  Read

Activators of Cylindrical Proteases as Antimicrobials: Identification and Development of Novel Small Molecule Activators of the ClpP Protease
Leung, E., Datti, A., Cossette, M., Goodreid, J., McCaw, S. E., Mah, M., Nakhamchik, A., Ogata, K., El Bakkouri, M., Cheng, Y.-Q., Wodak, S. J., Eger, B. T., Pai, E. F., Liu, J., Gray-Owen, S., Batey, R. A., & Houry, W. A.
Chemistry & Biology 18(9), 1167–1178 (2011)  Read

Linkage between the Bacterial Acid Stress and Stringent Responses Revealed by the Structure of the Inducible Lysine Decarboxylase
Kanjee, U., Gutsche, I., Alexopoulos, E., Zhao, B., El Bakkouri, M., Thibault, G., Liu, K., Ramachandran, S., Snider, J., Pai, E. F., & Houry, W. A.
The EMBO Journal 30(5), 931-944 (2011)  Read