Satpal Virdee's Research Group

Virdee Lab Website | Pubmed | Biography


Molecular mechanisms of E3 ligases in disease pathways

Our lab studies how ubiquitylation is carried out by unconventional E3 ligating enzymes (E3s), and how diseases might be treated by modulation of their activity. The E3s we have discovered have exposed an unexpected diversity to the ubiquitin system. We have uncovered novel ubiquitin transfer paradigms and challenged longstanding dogma regarding how ubiquitin is attached to substrates. For example, we showed the RING-Cys Relay (RCR) E3 MYCBP2 selectivity attaches ubiquitin to hydroxy amino acids. We also demonstrated that the MJD class of deubiquitylating enzymes (DUBs) selectively remove ubiquitin from these unconventional sites. This work has helped kickstart the exciting new field of non-lysine ubiquitylation. Importantly, these new principles are central to neurodegeneration, cancer, and infectious disease. Key to our discovery-based research is the development and application of chemical probes. Their deployment allows us to monitor proteome-scale changes in ubiquitin enzyme activity. We then use a multidisciplinary approach to investigate observations of medical importance. The work streams in our lab can be subdivided as follows:

  1. Discovery of mechanistically and architecturally novel E3 ligases
  2. Molecular mechanism of E3 ligase regulation and dysregulation in disease
  3. Chemical biology-based technology development
From the left: Lucy Barnsby, Virginia De Cesare, Sunil Mathur, Satpal Virdee, Adam Fletcher, Peter Mabbitt, Daniel Squair, Marc-Andre Dery
From the left: Lucy Barnsby, Virginia De Cesare, Sunil Mathur, Satpal Virdee, Adam Fletcher, Peter Mabbitt, Daniel Squair, Marc-Andre Dery

People

Daniel Squair | Research Assistant
Gaurav Beniwal | PhD Student
Hajra Bibi | PhD Student
Mehmet Gundogdu | Postdoctoral Researcher
Mathieu Soetens | Postdoctoral Researcher
Jiazhen Zhang | Postdoctoral Researcher

Selected Publications

  • Ahel, J., Fletcher, A., Grabarczyk, D. B., Roitinger, E., Deszcz, L., Lehner, A., Virdee, S. & Clausen, T (2021) E3 ubiquitin ligase RNF213 employs a non-canonical zinc finger active site and is allosterically regulated by ATP bioRxiv  
  • Barnsby-Greer, L., Mabbitt, P. D., Dery, M. A., Squair, D. R., Wood, N. T., Lange, S. & Virdee, S (2023) An Atypical E3 Ligase Module in UBR4 Mediates Destabilization of N-degron Substrates bioRxiv  
  • Squair DR, Virdee S (2022) A new dawn beyond lysine ubiquitination Nat Chem Biol 18 802-811 doi:10.1038/s41589-022-01088-2 PMID: 35896829
  • De Cesare V, Carbajo Lopez D, Mabbitt PD, Fletcher AJ, Soetens M, Antico O, Wood NT, Virdee S. (2021) Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases Proc Natl Acad Sci U S A 118 e2006947118 PMID: 33479176
  • Mabbitt, P. D., Loreto, A., Déry, M-A., Fletcher, A. J., Stanley, M., Pao, K-C., Wood, N. T., Coleman, M. P., & Virdee, S (2020) Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity Nat Chem Biol 16 1227-1236 PMID: 32747811
  • Mathur S, Fletcher AJ, Branigan E, Hay RT, Virdee S. (2020) Photocrosslinking Activity-Based Probes for Ubiquitin RING E3 Ligases. Cell Chem Biol 27 74-82 PMID: 31859248
  • Pao KC, Wood NT, Knebel A, Rafie K, Stanley M, Mabbitt PD, Sundaramoorthy R, Hofmann K, van Aalten DMF, Virdee S (2018) Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity Nature 556(7701) 381-385 PMID: 29643511
  • Pao, K. C., Stanley, M., Han, C., Lai, Y. C., Murphy, P., Balk, K., Wood, N. T., Corti, O., Corvol, J. C., Muqit, M. M., Virdee, S. (2016) Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation Nat Chem Biol 12 324-331 PMID: 26928937