DUBs employ different strategies to recognize polyubiquitin. In addition to cleaving ubiquitins off proteins, DUBs can also cleave between ubiquitinated moieties within a polyubiquitinated chain to edit the ubiquitin signal. Some DUBs display remarkable preference for cleaving polyubiquitin chains of certain linkage types.
However, how DUBs specifically recognize and hydrolyze different polyubiquitin chains is poorly understood. Recently a novel set of DUB probes was reported by Ovaa and co-workers. These probes enable you to study DUBs that use S2 pocket binding to modulate DUB activity and specificity.