UBC Dentistry

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

Teaching Areas:

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

BIOSKETCH November 2, 2022

Professor Christopher Overall was appointed a Tier 1 Canada Research Chair in Protease Proteomics and Systems Biology (2001) and a Senior Fellow of the Freiburg Institute of Advanced Studies, Albert-Ludwigs Universität Freiburg, Germany (2010–2013), where he is now an Honorary Professor (2014–). He was inducted as a fellow into the Royal Society of Canada, Academy of Science in 2018. He is best known for his development of proteomic methodology for the discovery of 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, as well as two new molecular correctors to cure MALT1 protease deficiency in a primary immunodeficiency. By generating clinically relevant insights into how proteases dampen disease-fighting defense 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.

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 work with Dr. Michael Smith, Nobel Laureate, Biotechnology Laboratory, UBC. During his Ph.D. Dr. Overall was awarded the International Association for Dental Research (I.A.D.R.) Edward H. Hatton Award (1987), the C.A.D.R. Student Research Award (1987), the A.A.D.R., William J. Gies Award (1989), and the Canadian Dental Research Foundation Award (1989). After starting his lab in the Faculty of Dentistry at UBC, Dr. Overall was then awarded the 1991 I.A.D.R. Young Investigator Award in recognition of the significant contribution to Dental Research by a Junior Investigator under the age of 35 years. More recently, he was awarded the International Association for Dental Research Distinguished Scientist Award (2013).

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 and is now a Creative Destruction Lab Scientist, UBC Sauder School of Business, and a consultant for Genentech, Novartis and several Biotechnology companies. He is a highly cited scientist (303 Career total referred publications and an h-index of 101, with >37,100 citations—including 54 >100-199, 28 >200-499, 11 >500-999, 3 >1,000-1,500, and 1>1,600, including 31 high-impact Nature (1), Science (2), Cell and daughter journal (28) papers, most as senior PI). He has disseminated his lab’s findings by > 259 keynote, plenary and invited talks at international and national conferences, and 235 invited seminars at universities, research institutes and companies. He has trained 40 postdoctoral fellows and graduated 14 Ph.D. and 6 M.Sc. students, with 18 now holding academic appointments: 8 are Full Professors (including 2 Department Chairs), 4 are Associate Professors, and 6 are Assistant Professors.

He was elected by his peers to organize and Chair the 2003 Matrix Metalloproteinase (MMP) and 2010 Protease Gordon Research Conferences, and in 2017 he was Co-Chair of the International Proteolysis Society Biannual Meeting, the premier conferences of his fields. He holds influential roles on the executive of > 10 international committees, the most prominent of which was being elected to the Human Proteome Organization (HUPO) Executive Council and to Chair the HUPO Chromosome-centric Human Proteome Project (C-HPP). In 2022 he was invited to attend the “G7 Research Summit on One Health” as UBC’s sole representative. He is the recipient of numerous awards e.g., 2006 Killam Faculty Research Prize, Senior Science UBC; 2002 CIHR Researcher of the Year Award; Helmholtz Award (2008); International Proteolysis Society Lifetime Achievement Award (2011); Matrix Biology Society of Australia and New Zealand Barry Preston Award (2012); and the International Association for Dental Research 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 highly prestigious 2018 international HUPO Discovery Award in Proteomics Sciences; and the 2022 Helmut Holzer Award. He is an Associate Editor of the Journal of Proteome Research.

Overall Laboratory Research Interests

Professor Chris Overall is a biochemist and molecular biologist with internationally recognised expertise in proteases, proteomics, and inflammation signalling. Only 340/565 human proteases have known substrates and hence biological roles (Nature Reviews Genetics). Recognizing the importance of substrate-binding exosite domains on proteases, I led a team that was the first to use these as substrate ‘baits’ in a yeast two-hybrid screen, at a time when protein disulphide cross-linkages were predicted to exclude two-hybrid screens for extracellular proteins (Science). We showed that MMPs were ill-conceived drug targets as MMPs were tissue protective, in an era when MMPs have always been considered drug targets (Nature Reviews Drug Discovery), by orchestrating neutrophil and macrophage leukocyte responses through coordinate activation/inactivation of virtually all chemokines and complement. Recently we showed that macrophage MMP12 both stimulates, then over time inactivates, anti-viral interferon-α (Nature Medicine) and interferon-γ (Nature Communications), providing feedback which also drives the transition from pro-inflammatory IFN-γ-activated (M1) macrophages to tissue-reparative immunosuppressant (M2) macrophages. more details...

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.

Christopher M. Overall

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