Ubiquitin Biology

Group picture 20110922
Group Site: 
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.

 


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.

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.

Mani Ravichandran
Mani Ravichandran, M.Sc.

Mani did her Master’s degree in Biochemistry with specialization in Clinical Biochemistry at Bharathiyar University, India. She worked as a lecturer in the Faculty of Biochemistry, Perundurai Medical College and Research Centre, India before joining the Biotechnology team at SGC Toronto in 2004. She is responsible for preparing in-house protein crystallization screens, protein purification, and crystallization.

Structures

Structure of the Season


PDB:3TUG HECT domain of ITCH E3 ubiquitin ligase (Deposited 2011-09-16)

Summary of SGC Solved Structures in Ubiquitin Biology


Publications

This list only includes ubiquitin-related publications.

Deubiquitinases:

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

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

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 [dot] tong[at]utoronto [dot] ca

Phone: 1-416-946-3870

Fax: 1-416-946-0588

Alumni

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
  • Lianet Lopez
  • Elena Newman
  • Hengran Cui
  • George Awakumov
  • 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.