UBC Dentistry

Christopher M. Overall

B.D.S., B.Sc. (Hons.), M.D.S., Ph.D., F.C.A.H.S., F.R.S.C.
Full Professor
Distinguished University Scholar, University of British Columbia
Canada Research Chair Laureate in Protease Proteomics and Systems Biology
Senator, University of British Columbia Senate
Yonsei Distinguished Scholar, Yonsei University
Honorary Professor, Albert-Ludwigs Universität Freiburg
Chair, Chromosome-Centric Human Proteome Project, Human Proteome Organization
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Publications Lab

Office:
Rm: Life Sciences Centre 4.401
2350 Health Sciences Mall
Tel: 604-822-2958
Fax: 604-822-7742

Lab:
Rm: Life Sciences Centre 4.420
2350 Health Sciences Mall
Tel: 604-822-3561
Fax: 604-822-7742

Research Areas:

Proteomics, degradomics, Human Proteome Project, proteases, Zoonotic Viruses, COVID-19, One Health, MMPs, anti-viral immunity, innate immunity

Teaching Areas:

Proteomics, degradomics, Human Proteome Project, connective tissue biochemistry and molecular biology,

BIOSKETCH, DR CHRISTOPHER M OVERALL (October 1, 2024)

Professor Christopher Overall is a Full Professor, Distinguished University Scholar and Canada Research Chair Laureate in Protease Proteomics and Systems Biology at the University of British Columbia; an Honorary Professor at Albert-Ludwigs Universität Freiburg, Germany, and a Yonsei Distinguished Scholar of Yonsei University, Seoul, Republic of Korea. He was a Senior Fellow of the Freiburg Institute of Advanced Studies, Albert-Ludwigs Universität Freiburg, Germany (2010–2013) and a Tier 1 Canada Research Chair in Protease Proteomics and Systems Biology (2001–2022). Dr Overall was inducted as a fellow into the Royal Society of Canada (FRASC) Academy of Science in 2018 and the Canadian Academy of Health Sciences (FCAHS) in 2005.

Dr. Overall completed his B.D.S., Honours Science and Master’s degrees at the University of Adelaide, South Australia; his Ph.D. in Biochemistry at the University of Toronto, Canada; and was an MRC Centennial Fellow in his postdoctoral training with Dr. Michael Smith, Nobel Laureate, Biotechnology Laboratory, UBC. He launched his lab at UBC in 1993. On sabbatical in 1997 – 1998, he was a Senior Scientist at British Biotech Pharmaceuticals, Oxford, UK, and in 2004 and 2008, a Senior Scientist at the Expert Protease Platform, Centre for Proteomic Drug Discovery, Novartis Pharma, Basel, Switzerland. He is now a Creative Destruction Lab Scientist at the UBC Sauder School of Business and a consultant for Genentech, Novartis and several Biotechnology companies.

Chris is best known for developing proteomic methodology to discover protease substrates in vivo, thereby establishing the field of degradomics. He has used these techniques to reveal new biological roles for proteases in immunity and disease, most recently in the COVID-19 pandemic by SARS-CoV-2 proteases, developing two new molecular correctors to cure MALT1 protease deficiency in a primary immunodeficiency, and now in One Health Strategies for investigation of viral zoonosis. By generating clinically relevant insights into how proteases dampen disease-fighting defence systems involved in inflammation and immunodeficiency, degradomics has revealed an unexplored layer of complexity in the hierarchy of cell and immune regulation, greatly adding to our understanding of protease function and drug targeting.

He is a highly cited scientist of his 314 publications, with an h-index = 108 and >41,350 citations—including 70 >100 – 199, 29 >200 – 499, 13 >500 – 999, 3 >1,200 – 1,500, and 1>1,700, including 31 high-impact Nature (2), Science (2), Cell and daughter journal (27) papers, most as senior PI. He has disseminated his lab findings by > 296 keynote, plenary, and invited talks at international and national conferences, as well as 250 invited seminars at universities, research institutes, and companies. He has mentored 61 trainees (40 PDF / 14 Ph.D. / 7 M.Sc.) with great success: 9 of whom are Full Professors (including 2 Department Chairs), 5 are Associate Professors, and 6 are Assistant Professors. Indeed, Chris was awarded the UBC John McNeill Excellence in Health Research Mentorship Award in 2023.

His peers elected Dr. Overall to organize and chair the premier conferences in his field, including the 2003 Matrix Metalloproteinase and 2010 Protease Gordon Research Conferences, and in 2017, he co-chaired the International Proteolysis Society Biannual Meeting. He holds influential roles on the executive of >10 international committees, the most prominent of which was election to the Human Proteome Organization (HUPO) Executive Council and as Chair of the HUPO Chromosome-centric Human Proteome Project (C-HPP). In 2022, he was invited to represent UBC at the G7 Research Summit on One Health. He has received numerous recognitions, e.g., election to the Royal Society of Canada, appointment as a Yonsei Distinguished Scholar (Yonsei University, 2023) and a Distinguished University Scholar of UBC in 2024. He received the UBC 2006 Killam Faculty Research Prize; the 2002 Canadian Institutes of Health Research (CIHR) Researcher of the Year; the Helmholtz Award (2008); International Proteolysis Society Lifetime Achievement Award (2011); Matrix Biology Society of Australia and New Zealand Barry Preston Award (2012); and the IADR Distinguished Scientist Award (2013). His advances in proteomics have been recognized by the Canadian National Proteomics Network Tony Pawson Award (2014); the Proteomass Scientific Society Award (2017); the 2018 Human Proteome Organization (HUPO) Discovery Award in Proteomics Sciences; and the 2022 Helmut Holzer Award. He is a Councilor of 1st -Hub Global Proteomics Project, Guangzhou, China (2023 – ).

1. McQuibban, G.A., Gong, J.-H., Tam, E., McCulloch, C.A.G., Clark-Lewis, I., and Overall, C.M. 2000. Inflammation Dampened by Gelatinase A Cleavage of Monocyte Chemoattractant Protein-3. Science 289, 1202-1206.
2. Overall, C.M. and Kleifeld, O. 2006. Validating MMPs as Drug Targets and Anti-Targets for Cancer Therapy. Nature Reviews Cancer 6, 227-239.
3. Marchant, D.J., Bellac, C., Moraes, T.J., Wadsworth, S.J., Dufour, A., Butler, G.S., Bilawchuk, L.M., Hendry, R.G., Robertson, A.G., Cheung, C.T., Ng, J., Ang, L., Luo, Z., Heilbron, K., Norris, M.J., Duan, W., Bucyk, T., Karpov, A., Devel, L., Georgiadis, D., Hegele, R.G., Luo, H., Granville, D.J., Dive, V., McManus, B.M., and Overall, C.M. 2014. A New Transcriptional Role for Matrix Metalloproteinase-12 in Antiviral Immunity. Nature Medicine 20, 493 – 502.
4. Dufour, A., Bellac, C.L, Eckhard, U., Solis, N., Klein, T., Kappelhoff, R., Fortelny, N., Jobin, P., Rozmus, J., Mark, J., Pavlidis, P., Dive, V., Barbour, S.J., and Overall, C.M. 2018. C-Terminal Truncation of IFN-γ Inhibits Proinflammatory Macrophage Responses and is Deficient in Autoimmune Disease. Nature Communications 9: 2416, 1–18.
5. Puente, X.S., Sanchez, L.M., Overall, C.M., and López-Otín, C. 2003. Human and Mouse Proteases: A Comparative Genomic Approach. Nature Reviews Genetics 4, 544-558.
6. López-Otín, C. and Overall, C.M. 2002. Protease Degradomics: A New Challenge for Proteomics. Invited Review. Nature Reviews Molecular Cell Biology 3, 509-519.

Dr. Overall coined the term degradomics for the “omics” analyses of proteases (Nature Reviews Molecular Cell Biol). Defining protease substrate cleavage-site specificity is central to protease characterization and linkage to substrates. In this way we developed the only peptide library proteomics technique to identify both the P’ and P cleavage sequences—Proteomic Identification of Cleavage Specificity (PICS) (Nature Biotechnology; Nature Protocols). We used PICS to demonstrate the unsuspected occurrence of an active metallopeptidase in bacterial flagellin (Nature Commun).

In conventional proteomics, 100,000s of trypsin-generated peptides of a proteome dominated by abundant proteins dilutes the terminal peptides of protein N- and C-ends and protease-generated ‘neo’-termini, rendering cleaved peptides rarely detectable. Terminal Amino Isotopic Labelling of Substrates (TAILS) circumvents these issues in a powerful high-throughput method. TAILS purifies protein N-terminal peptides and cleaved neo-N-terminal peptides using innovative polymers-for-proteomics to simultaneously identify cleavage sites and hence substrates in native proteomes (Nature Biotechnology; Nature Protocols). Protein C-termini are difficult to label chemically en route to identification, and hampered by their absence of basic residues following trypsin digestion. We discovered a new protease in Archaea, LysargiNase, to address this (Nature Methods). LysargiNase-digested proteins release C-terminal peptides that retain a N-terminal lysine or arginine enabling their identification by his C-TAILS technique (Nature Methods). To analyze natural and neo-termini, we developed the Termini-orientated protein Function INferred Database (TopFIND) (Nature Methods).

7. Schilling, O. and Overall, C.M. 2008. Proteome-Derived Database-Searchable Peptide Libraries for Identifying Protease Cleavage Sites. Nature Biotechnology 26, 685-694.
8. Eckhard, U., Bandukwala, H., Mansfield, M.J., Marino, G., Cheng, J., Wallace, I., Holyoak, T., Charles, T.C., Austin, J., Overall, C.M.^, and Doxey, A.C.^ 2017. Discovery of a Proteolytic Flagellin Family in Diverse Bacterial Phyla that Assembles Enzymatically Active Flagella. Nature Communications 8: 521, 1 – 9.
9. Kleifeld, O., Doucet, A., auf dem Keller, U., Prudova, A., Schilling, O., Kainthan, R.K., Starr, A., Foster, L.J., Kizhakkedathu, J.N., and Overall, C.M. 2010. Isotopic Labelling of Terminal Amines in Complex Samples Identifies Protein N-Termini and Protease Cleavage Products. Nature Biotechnology 28, 281-2886.
10. Huesgen, P.F., Lange, P.F., Rogers, L.D., Solis, N., Eckhard, U., Kleifeld, O., Goulas, T., Gomis-Rüth, F.X., and Overall, C.M. 2015. LysargiNase Mirrors Trypsin for Protein C-Terminal Identification. Nature Methods 12, 55-58.
11. 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.
12. Lange, P. and Overall, C.M. 2011. TopFIND, a Knowledgebase Linking Protein Termini with Function. Nature Methods 8, 703-704.

Dr. Chris Overall leads a team to explore the roles of the protease MALT1, an essential transducer in lymphocyte receptor signalling and immune activation (Nature Communications). We found that independent of proteolytic cleavage, non-proteolytic scaffolding protein-protein interactions by MALT1 initiate NFκB activation, with MALT1 proteolytic activity later cleaving HOIL1 in the Linear Ubiquitin Assembly Complex (LUBAC) to downregulate linear ubiquitination, so terminating NFκB signaling (Nature Communications). This inspired the development of a novel molecular corrector to specifically replace the mutant side-chain in the immunodeficient patient, restoring activity and immune function (Nature Chemical Biology). More recently, using a novel protease substrate predictor developed in the Overall Lab, GO-2-Substrates, his group identified and validated seven new MALT1 substrates and 13 candidate substrates in human cells.

13. Klein, T., Fung, S.Y., Renner, F., Blank, M.A., Dufour, A., Kang, S., Bolger-Munro, M., Scurll, J.M., Priatel, J.J., Schweigler, P., Melkko, S., Gold, M.S., Viner, R.I., Régnier, C.H., Turvey, S.E., and Overall, C.M. 2015. The Paracaspase MALT1 Cleaves HOIL1 Reducing Linear Ubiquitination by LUBAC to Dampen Lymphocyte NF-κB Signalling. Nature Communications 6: 8777, 1-17.
14. Quancard, J., Klein, T., Fung, S-Y., Renatus, M., Hughes, N., Israël, L., Priatel, J.J., Kang, S., Blank, M.A., Viner, R.I., Blank, J., Schlapbach, A., Erbel, P., Kizhakkedathu, J., Villard, F., Hersperger, R., Turvey, S.E., Eder, J., Bornancin, F., and Overall, C.M. 2019. An Allosteric MALT1 Inhibitor is a Molecular Corrector Rescuing Function in an Immunodeficient Patient. Nature Chemical Biology 15, 304 – 313. doi 10.1038/s41589-018-0222-1.
15. Bell, P.A., Scheuermann, S., Renner, F., Pan, C.L., Lu, H.Y., Turvey, S.E., Bornancin, F., Régnier, C.H., and Overall, C.M. 2022. Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates. Computational and Structural Biotechnology Journal 20, 4,717 – 4,732.

Most recently, Chris Overall is investigating the host cell responses to SARS-CoV-2 and zoonotic viruses. By using TAILS degradomics, his team has discovered >300 substrates of SARS-CoV-3 3CLpro main protease and their roles in pathogenesis and viral escape from immune responses and host cell defenses.

16. Pablos, I., Machado, Y., de Jesus, H.C.R., Mohamud, Y., Kappelhoff, R., Lindskog, C., Vlok, M., Bell, P.A, Butler, G.S., Grin, P.M., Cao, Q.T., Nguyen, J.P., Solis, N., Abbina, S., Rut, W., Vederas, J.C., Szekely, L., Szakos, A., Drag, M., Kizhakkedathu, J., Mossman, K., Hirota, J., Jan, E., Lou, H., Banerjee, A., and Overall, C.M. 2021. Mechanistic Insights into COVID-19 by Global Analysis of the SARS-CoV-2 3CLpro Substrate Degradome. Cell Reports 37, (4):109892. doi: 10.1016/j.celrep.2021.109892.