Welcome to !




















Professor Christopher M Overall
University of British Columbia, Departments of Oral Biological and Medical Sciences, Faculty of Dentistry/ Biochemistry and Molecular Biology, Faculty of Medicine and
CIHR Group in Matrix Dynamics, UBC Blood Protein Centre, UBC Prostate Centre, Protein Engineering Network Centres of Excellence, Canadian Arthritis Network
2199 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada
Email: chris.overall@ubc.ca
Tel: +1 (604) 732-5989
Fax: +1 (604) 822-3562
Homepage: http://www.clip.ubc.ca

Research
Chris Overall?s research interests focus on protease proteomics, protein:protein interactions of MMPs with substrates and their natural inhibitors termed TIMPs, the cellular activation mechanisms of MMPs, and more recently on developing "degradomics" approaches to discover novel MMP substrates on a proteome-wide scale. He has published over 70 scientific papers and 10 book chapters with recent publications in ?Science?, ?Nature Genetics?, ?Nature Neuroscience?, "Nature Reviews Cancer", and "Nature Reviews Molecular Cell Biology". Much of my work has centered on dissecting protein-protein interactions involved in MMP substrate binding and activation. Several of these works presented comprehensive mutagenesis studies that mapped binding sites. This work is characterized by utilization of a wide variety of approaches to tackle fundamental issues of proteolysis including biochemical assays, enzyme kinetics, cell culture and ex vivo techniques, animal models including knock out mice, structural biology and most recently, proteomic and genomic approaches. My lab has recently completed the design and manufacture of the first complete human protease and inhibitor chip?the CLIP-CHIP, a work that was facilitated by a powerful collaboration with Dr Carlos Lopez-Otin, Spain, in which they annotated and compared the entire human and murine protease degradomes. A large focus of our present work is developing novel degradomics screens to search for new substrates including "exosite scanning", which led to the discovery that chemokines are novel MMP substrates, converting chemokine agonists to antagonists that profoundly suppress inflammation in vivo, and inactive catalytic domain capture (ICDC). Our most recent work uncovered an entirely novel neurodegenerative pathway that is initiated by HIV-1 infection and that leads specifically to neuronal apoptosis and HIV dementia after chemokine cleavage in the brain by MMP-2. The substrates discovered by these approaches, that broke new ground in the use of the yeast two-hybrid system, is resulting in a paradigm shift in the role of MMPs in vivo?an important family of proteases traditionally associated with extracellular matrix remodelling. Our work in discovering up to 30 new substrates that are important signalling molecules, reveals that MMPs are critical signalling proteases that operate in a wide variety of diseases. Our present work in protease proteomics is harnessing the power of mass spectrometry to discover myriads of new substrates in a facile manner. Current and new Isotope Coded Affinity Tags (ICAT) are being used with inline multidimensional liquid chromatography MS/MS to identify protease substrates o a system-wide basis in complex biological environments such as cell culture. Hence, by identifying the protease substrate degradome, we hope to uncover the in vivo role of proteases and thereby validate new drug targets.
Collaborations
Carlos Lopez-Otin
Sharon Stack
Chris Power
Chris McCullouch
Arun Seth
Publications
Schilling, O., Barré, O., Huesgen, P.F., and Overall, C.M. 2010. Proteome-wide Analysis of Protein Carboxy Termini: C Terminomics. Nature Methods 7, 508-511. Featured in C&EN (Chemical and Engineering News)

Kleifeld, O., Doucet, A., auf dem Keller, U., Prudova, A., Schilling, O., Kainthan, R.K., Starr, A., Foster, L.J., Kizhakkedathu, J.N., Overall, C.M. 2010. Isotopic labeling of Terminal Amines in Complex Samples Identifies Protein N-termini and Protease Cleavage Products. Nature Biotechnology 28, 281-288

Schilling, O. and Overall, C.M. 2008. Proteome-derived Database Searchable Peptide Libraries for Identifying Protease Cleavage Sites. Nature Biotechnology 26, 685-694

Prudova, A., auf dem Keller, U., Butler, G.A., and Overall, C.M. 2010. Multiplex N-Terminome Analysis of MMP-2 and MMP-9 Degradomes by iTRAQ-TAILS Quantitative Proteomics. Molecular Cellular Proteomics 9, 894-911

auf dem Keller, U., Prudova, A., Gioia, M., Butler, G.S., and Overall, C.M. 2010. A Statistics Based Platform for Quantitative N-Terminome Analysis and Identification of Protease Cleavage Products. Molecular Cellular Proteomics 9, 912-927

Doucet, A., Butler, G.S., Rodríguez, D., Prudova, A., and Overall, C.M. 2008. Metadegradomics: Towards Quantitative Degradomics of Proteolytic Post-Translational Modifications of the Cancer Secretome. Molecular Cellular Proteomics 7, 1925-1951

Butler, G.S. and Overall, C.M. 2009. Proteomic Identification of Multitasking Proteins in Unexpected Locations Complicates Drug Targeting. Nature Reviews Drug Discovery 8, 935-948. Featured Cover Photo

Overall, C.M. and Blobel, C.P. 2007. In Search of Partners: Linking Extracellular Proteases to Substrates. Nature Reviews Molecular Cell Biology 8, 245-257

Butler, G.S., and Overall, C.M. 2009. Updated Biological Roles for MMPs and New “Intracellular” Substrates Revealed by Degradomics. Biochemistry 48, 10,830-10,845





Questions/suggestions? Please contact the Network Administrator.
Copyright © by International Protease Network All Right Reserved.