A paper published in the September 2012 issue of Nature reveals, for the first time, how enzymes stimulate the transfer of ubiquitin, the protein that plays a critical role in the proper functioning of cells and therefore in the development of disease. Professor Ron Hay of the Division of Gene Regulation and Expression at the College of Life Sciences, University of Dundee and Professor Jim Naismith of the University of St. Andrews led the study in which the ubiquitin stimulating mechanism has been revealed at high resolution by Dr. Anna Plechanovova.
Professor Hay explained, “Cells in our body are controlled by switches that turn the activity of key proteins on or off. This can be done by tagging them with ubiquitin, another small protein. As the cell contains many thousands of proteins selecting the correct protein for ubiquitin tagging is critical. Ubiquitin modification is achieved by the sequential action of 3 enzymes: an E1 activating enzyme that links ubiquitin to a cysteine residue in an E2 conjugating enzyme and E3 ubiquitin ligases that catalyse the transfer of the ubiquitin from the E2~ubiquitin onto the substrate protein. There are more than 600 human genes that encode ubiquitin E3 ligases and as they influence almost all aspects of biological activity they often play critical roles in the development of disease.”
By far the most common E3 ligases belong to the RING family but how they stimulate ubiquitin transfer has been a long-standing mystery. This mystery has now been solved and the mechanism revealed at high resolution by Anna Plechanovova and colleagues in Ron Hay’s lab along with collaborator Jim Naismith at the University of St Andrews.
To accomplish this they determined the crystal structure of the RNF4 RING E3 ligase bound to ubiquitin linked E2. This gives a view of an E3 ligase, E2~ubiquitin complex primed for catalysis and suggests a unified mechanism for ubiquitin transfer that could apply to most other E3 enzymes. The RNF4 ubiquitin ligase plays a key role in arsenic therapy for acute myeloid leukaemia and related ubiquitin ligase Mdm2 controls the activity of p53, the “Guardian of the Genome”.
Ubiquitin E3 ligases are under close scrutiny in the pharmaceutical industry as potential drug targets and understanding the atomic details of the reaction mechanism will aid in the development of inhibitors that may have therapeutic value in a number of diseases. The paper, Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis, Anna Plechanovová, Ellis G. Jaffray, Michael H. Tatham, James H. Naismith & Ronald T. Hay, Nature 489, 115–120 (06 September 2012) is therefore expected to have a huge impact on both academic and commercial drug discovery.