Protein Ubiquitination in Eukaryotic Biology

Ubiquitin is a small, conserved protein present in all eukaryotes. The cell uses ubiquitin to modify proteins and modulate their functions. When a protein substrate is modified by a chain of multiple ubiquitin molecules, it will be taken to the proteasome for degradation. Ubiquitin-dependent protein degradation is involved in the regulation of many important and diverse proteins in the cell.

Ubiquitin E3 Ligases

Ubiquitin ligases are integral components of the ubiquitination process. At the end of a three-enzyme (E1-E2-E3) cascade, the ubiquitin E3 ligase mediates the transfer of a ubiquitin from the ubiquitin E2 conjugating enzyme to the protein substrate and dictates the specificity of the reaction. One particular ubiquitin ligase usually can only bind one or a limited set of protein substrates. Given the large number of proteins that are controlled by ubiquitin-dependent proteolysis, it is expected that there are hundreds of different ubiquitin ligases in human cells.

Ubiquitin Ligases as Drug Targets

As an emerging family of enzymes playing a central role in eukaryotic biology, ubiquitin ligases represent a novel class of potential drug targets. Can we use small molecules to manipulate ubiquitin ligases for therapeutic purpose? For example, can we inhibit the ubiquitination and degradation of a tumor suppressor? By revealing the atomic details of how various ubiquitin ligases function, our studies are aimed at establishing the structural framework and chemical basis for achieving these goals.


  • Zhou F, Lin Q, Zhu L, Ren Y, Zhou K, Shabek N, Wu F, Mao H, Dong W, Gan L, Ma W, Gao H, Chen J, Yang C, Wang D, Tan J, Zhang X, Guo X, Wang J, Jiang L, Liu X, Chen W, Chu J, Yan C, Ueno K, Ito S, Asami T, Cheng Z, Wang J, Lei C, Zhai H, Wu C, Wang H*, Zheng N*, Wan J*. 2013. D14-SCFD3-dependent degradation of D53 regulates strigolactone signalling. Nature. 504:406-10. (*Co-correspondence).

















  • Li T, Pavletich NP, Schulman BS, & Zheng N 2005. High-Level Expression and Purification of Recombinant SCF ubiquitin Ligases. Ed. Raymond J. Deshaies. Methods in Enzymol. 398: 125-142