Mechanism of poly-SUMO chain recognition by the ubiquitin ligase RNF4

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Post-translational modification is a chemical change to a protein after it has already been synthesised within a cell. This step enables the cell to 'mark' certain proteins so that their behaviour can be later controlled. Ubiquitin (Ub) and Small ubiquitin-like modifiers (SUMOs) form a family of proteins that are chemically attached to and removed from proteins in order to modify their function. SUMOs are involved in three important processes within the cell: they play crucial roles in regulating cell multiplication; are involved in how cells respond to damage to their genetic material (DNA); and control which genes are "switched on" or "switched off" in response to the environment. Diseases such as cancer arise when a series of unwelcome changes occur in some of these cellular processes, causing the cell to multiply out of control. Before we can identify what goes wrong in cancers it is necessary to understand exactly how our cells normally work. In this proposal two teams of researchers from the groups of Prof Steve Matthews (Imperial College) and Ron Hay (Dundee) have linked up to decipher how poly-SUMO protein chains are recognised and the downstream effects are elicited. The focus is on characterising the mechanism of substrate recognition by RNF4. RNF4 is a small protein that specifically recognises poly-SUMO chains on proteins and then attaches Ub to these substrates, which subsequently targets them to the proteasome for degradation. Regions of RNF4 contain SUMO interaction motif (SIMs) that 'fish-out' poly-SUMO chains. By using nuclear magnetic resonance (NMR), the shape and flexibility of protein complexes will be imaged in solution. Insight from these structural studies will be used to understand the features that control poly-SUMO recognition. This will shed light on the mechanisms that underlie fundamental aspects of cellular regulation, and the aberrant pathways that can lead to disease and cancer. In turn, this could lead to new ways of treating many types of cancer, for example, by developing drugs that block the activity of certain molecules that regulate SUMO activity.