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Three generations of DUB probes
April 27, 2016

S2 pocket on your DUB?

New DUB probes allow you to study DUBs that use S2 ubiquitin pocket binding to modulate DUB activity.

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.
 

three generations of activity-based DUB probes
 

1st generation

These probes target the S1 pocket and have contributed greatly to our understanding of DUBs. 

However these probes provide limited information on how DUBs process polyubiquitin chains.
probes catalogue
 

2nd generation

Di-ubiquitin-based probes with an electrophilic group between the two ubiquitins have been developed to capture DUBs with ubiquitins positioned in the S1 and S1’ pockets.
di-ubiquitin probes catalogue
 

new: 3rd generation

Di-ubiquitin probes that target the S1 and S2 pocket.

These will be useful tools to identify DUBs that rely on S2 site interactions to fine tune their activity.
more info tailor-made
 

Reference 

Non-hydrolyzable Diubiquitin Probes Reveal Linkage-Specific Reactivity of Deubiquitylating Enzymes Mediated by S2 Pockets 

Dennis Flierman,* Gerbrand J. van der Heden van Noort,* Reggy Ekkebus,* Paul P. Geurink,* Tycho E. T. Mevissen,** Manuela K. Hospenthal,** David Komander,** and Huib Ovaa*. Cell Chemical Biology, April 2016, Volume 23, Issue 4, p472–482, 21 April 2016,DOI: 10.1016/j.chembiol.2016.03.009

* The Netherlands Cancer Institute, Amsterdam, the Netherlands
** Cambridge Biomedical Campus, Cambridge, UK