A prerequisite for the E3-independent reaction is the presence of a Ub-binding domain (UBD) in the protein that is able to recognize Ub. This type of protein is of utmost importance for the cell because it can distinguish between ubiquitinated and non-ubiquitinated proteins, explains Dr. Daniela Hoeller, the responsible scientist. UBD-proteins are the key to the effects of Ub both in normal and malignant cells.

Dikic and his coworkers demonstrated that proteins equipped with an UBD can ubiquitinate themselves by directly recruiting Ub-loaded E2 enzymes thus making E3 ligases dispensible. In their previous work Hoeller and Dikic showed that the ubiquitination of UBD proteins does not lead to their degradation but rather causes their functional inactivation. In other words they become unable to recognize and control ubiquitinated proteins. If needed the cell can re-activated them by cleaving the attached Ub. In this way the cell can quickly and dynamically react on external signals.

The discovery provides the basis for novel therapeutic approaches that are more specific than drugs like Bortezomib. For an effective therapeutic use there is still a long way to go, explains Mller-Esterl, who needs to update his biochemistry textbook now.