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Ubiquitin Biology

Group picture 20110922
Group Site: 
toronto
Group Leader: 

Dr. Yufeng Tong,  previously Dr. Sirano Dhe-Paganon

Group Info

Research Areas

Ubiquitylation is an important post-translational modification process that covalently links ubiquitin to the lysine side chain of the target protein. Classical Lys48-linked polyubiquitylation directs protein degradation through the proteosome pathway and is essential for protein turn over and many cellular processes. The discovery of the ubiquitin-proteosome pathway was awarded the 2004 Nobel Prize in Chemistry. More recently, the importance of non-classical ubiquitylation mechanisms has come to light, with the recognition of large numbers of enzymes involved in protein ubiquitylation and deubiquitylation. The ubiquitin pathway contributes to an unprecedented range of biological processes, including  membrane protein endocytosis, DNA repair, cell signaling, autophagy, apoptosis, immune response and inflammation, viral infection, -- just to name a few. Misregulation of the ubiquitylation process has been related to many human diseases including cancers, diabetes, hypertension, and neurological diseases like autism, Parkinson’s disease.

 

The Ubiquitin Biology Group at SGC-Toronto focuses on understanding the structure, function, specificity, and enzymatic mechanism of HECT-type E3 ubiquitin ligases and ubiquitin-specific proteases. We utilize the SGC’s established high-throughput structural biology platform for protein production, structure determination and biochemical assays to probe the function of these enzymes. We will also collaborate extensively with other groups to identify small molecules and biomolecules that will alter the activity of disease-related ligases and proteases.

 

 

Structures

Structure of the Season


PDB:4JUY, PUB domain of RNF31 E3 ubiquitin ligase (Deposited 2013-03)

 

 

 

Group Members
Yufeng Tong, Ph.D.

Yufeng holds a B.Sc. degree in chemistry from Tsinghua University,  Beijing and a Ph.D. in Molecular Biology and Biochemistry from the Institute of Biophysics, Chinese Academy of Sciences.  He worked as a postdoc in the Case Western Reserve University to study the structure and function of the ubiquitin-like domain of plexin B1 before he joined SGC in 2006.  During his postdoc training in SGC, he contributed to more than 60 crystal structures. Yufeng is currently an SGC fellow and the team leader of the Ubiquitin Biology program in SGC Toronto. 

Michelle Ong, Ph.D.
Michelle Ong, Ph.D.

Michelle completed her Ph.D. study in the laboratory of Assistant Professor Curt Davey at the Nanyang Technological University in Singapore. She joined the SGC in 2011 as a post-doctoral fellow under the direction of Professor Cheryl Arrowsmith.　Michelle is currently working on histone ubiquitylation and deubiquitylation.

Jicheng Hu, Ph.D.

Jicheng received his PhD degree in Biochemistry and Molecular Biology from Peking University and had postdoctoral training at Peking University with Dr. Bin Xia. In Jan. 2012, Jicheng joined the ubiquitin biology group at SGC. He currently works on the structure and function of HECT-type E3 ubiquitin ligases and ubiquitin-specific proteases.

Johnny Guan, M.Sc

Johnny holds a Master of Science degree from University of Toronto, and is currently working as lab technician in the ubiquitin biology group.

Publications

A complete list of publications by Dr. Tong can be found at ResearcherID.com

 

The following list only includes ubiquitin-related publications by the SGC Ubiquitin Biology program (formerly led by Dr. Sirano Dhe-paganon).

Deubiquitinases:

 

Avvakumov G.V., Walker J.R., Xue S., Allali-Hassani A., Asinas A., Nair UB, Fang X, Zuo X, Wang YX, Wikinson KD, Dhe-Paganon S. (2012) Two ZnF-UBP Domains in Isopeptidease T (USP5). Biochemistry 51:1188-1198.

Edelmann M.J., Iphofer A., Akutsu M., Altun M., di G.K., Kramer H.B., Fiebiger E., Dhe-Paganon S., and Kessler B.M. (2009). Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J 418: 379-390.

Avvakumov G.V., Walker J.R., Xue S., Finerty P.J., Jr., MacKenzie F., Newman E.M., and Dhe-Paganon S. (2006). Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). J Biol Chem. 281: 38061-38070.

E1 ubiquitin-activating enzyme

Bacik J.P., Walker J.R., Ali M., Schimmer A.D., and Dhe-Paganon S. (2010). Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme. J Biol Chem. 285: 20273-20280.

Xu G.W., Ali M., Wood T.E., Wong D., Maclean N., Wang X., Gronda M., Skrtic M., Li X., Hurren R. et al. (2010). The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood 115: 2251-2259.

E2 conjugating enzymes

Ceccarelli D.F., Tang X., Pelletier B., Orlicky S., Xie W., Plantevin V., Neculai D., Chou Y.C., Ogunjimi A., Al-Hakim A. et al. (2011). An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145: 1075-1087.

Ko S., Kang G.B., Song S.M., Lee J.G., Shin D.Y., Yun J.H., Sheng Y., Cheong C., Jeon Y.H., Jung Y.K. et al. (2010). Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity. J Biol Chem. 285: 36070-36080.

E3 ligases

 

Lemark A, Yee A, Bezsonova I, Dhe-Paganon S, Arrowsmith CH. (2011) Zn-binding AZUL domain of human ubiquitin protein ligase Ube3A. J Biomol NMR 51:185-190

Shloush J., Vlassov J.E., Engson I., Duan S., Saridakis V., Dhe-Paganon S., Raught B., Sheng Y., and Arrowsmith C.H. (2011). Structural and functional comparison of the RING domains of two p53 E3 ligases, Mdm2 and Pirh2. J Biol Chem. 286: 4796-4808.

Soss S.E., Yue Y., Dhe-Paganon S., and Chazin W.J. (2011). E2 conjugating enzyme selectivity and requirements for function of the E3 ubiquitin ligase CHIP. J Biol Chem. 286: 21277-21286.

Bezsonova I., Walker J.R., Bacik J.P., Duan S., Dhe-Paganon S., and Arrowsmith C.H. (2009). Ring1B contains a ubiquitin-like docking module for interaction with Cbx proteins. Biochemistry 48: 10542-10548.

Ubiquitin-like domains

Wang H., Hota P.K., Tong Y., Li B., Shen L., Nedyalkova L., Borthakur S., Kim S., Tempel W., Buck M. et al. (2011). Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). J Biol Chem. 286: 26093-26106.

Tong Y., Chugha P., Hota P.K., Alviani R.S., Li M., Tempel W., Shen L., Park H.W., and Buck M. (2007). Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem. 282: 37215-37224.

Ubiquitin and Epigenetics

Nady N., Lemak A., Walker J.R., Avvakumov G.V., Kareta M.S., Achour M., Xue S., Duan S., lali-Hassani A., Zuo X. et al. (2011). Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J Biol Chem. 286: 24300-24311.

Syeda F., Fagan R.L., Wean M., Avvakumov G.V., Walker J.R., Xue S., Dhe-Paganon S., and Brenner C. (2011). The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. J Biol Chem. 286: 15344-15351.

Bronner C., Fuhrmann G., Chedin F.L., Macaluso M., and Dhe-Paganon S. (2010). UHRF1 Links the Histone code and DNA Methylation to ensure Faithful Epigenetic Memory Inheritance. Genet Epigenet. 2009: 29-36.

Avvakumov G.V., Walker J.R., Xue S., Li Y., Duan S., Bronner C., Arrowsmith C.H., and Dhe-Paganon S. (2008). Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455: 822-825.

Ubiquitin and Proteosome

 

Ouyang H, Ali YO, Ravichandran M, Dong A, Qiu W, MacKenzie F, Dhe-Paganon S, Arrowsmith CH, Zhai RG. (2012) Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitn C termini. J Biol Chem 287:2317-2327.

Qiu L., Pashkova N., Walker J.R., Winistorfer S., lali-Hassani A., Akutsu M., Piper R., and Dhe-Paganon S. (2010). Structure and function of the PLAA/Ufd3-p97/Cdc48 complex. J Biol Chem. 285: 365-372.

 

Contact

We are located on the 7th floor of the MaRS building (101 College St, Toronto) , South Tower.

Email: yufeng.tong@utoronto.ca

Phone: 1-416-946-3876

Fax: 1-416-946-0588

Alumni

Alumni from Dr. Tong's group.

  • Muhammad Bashir Khan, Ph.D.
    Dr. Khan worked in SGC from April 2012 to March 2013.
  • Hui Wang, Ph.D.
    Dr. Hui Wang completed her PhD study in Biological Chemistry from the University of Hong Kong. She joined the cell signalling group at SGC Toronto in 2008. After 10 months' personal leave, Dr. Wang worked in SGC for 6 months from Oct. 2011 as a causual employee.
  • Elena Dobrovetsky, M.Sc.
    Elena received her M.Sc. degree in Biological Macromolecular Crystallography from the Schulich Faculty of Chemistry, Technion - Israel Institute of Technology. She worked as a research technician in membrane proteomics from Aug. 2002 in Prof. Aled Edwards's lab before she joined SGC in 2007. Elena worked in the Ubiquitin Biology group from July - December, 2012 and rejoined the biotech group since then.

Previous members in Dr. Sirano Dhe-Paganon's group made great contribution to solve the structures of protein targets in ubiquitin biology and to the publication of many high-profile papers:

Postdoctoral Fellows:

  • Masato Akutsu
  • Abdalin Asinas
  • John-Paul Bacik
  • Irina Bezsonova
  • Tara Davis
  • Xudong Huang
  • Dene Littler
  • Paola Llinasgarcia
  • Dante Neculai
  • Liyan Qiu
  • Farisa Syeda
  • Leanne Wybenga

Technicians And Research Associates:

  • Denis Alenkin
  • George Awakumov
  • Hengran Cui
  • Lianet Lopez
  • Elena Newman
  • Sheng Xue
  • Laila Yermek

Students:

  • Nikesh Adenuri
  • Ryan Doherty
  • Shariq Mujib
  • Kathrine Ng
  • Ragika Paramanathan
  • Ravikiran Ravulapalli
  • Max Ruzanov
  • Yulia Slessarev
  • Amada Tharmalingam
  • Anders Vesterberg

Special thanks also go to Dr. John R. Walker, and Christine Butler from the core service groups for the excellent crystallgraphy and cloning services provided.