Structural Biochemistry/Enzyme/Deubiquitinating Proteases

Deubiquitinating Proteases are a group of enzymes that manage the post-translational modification of proteins formed by ubiquitylation and are regulatory in cell pathways. These deuquitinases (DUBs) cleave the ubiquitin-bonded proteins reversing signaling or it can also lead to protein stability. Komander, David, Michael J. Clague, and Sylvie Urbé. "Breaking The Chains: Structure And Function Of The Deubiquitinases." Nature Reviews Molecular Cell Biology 10.8 (2009): 550-563. Structure The Deubiquitinating protease families depend upon "two or three crucial amino acid residues", they making up a catalytic diad or triad. A nucleophilic attack of the isopeptide linkages is accomplished by a His side chain near the diad or triad lowers the pKa. An additional residue (often, Asn, or Asp) can polarize the catalytic His, but this is not always necessary for activity, an is only present in some of the DUB families. All the DUB families include divergent folds as well as many unstructured loops. The different families of DUBs have different domains that allow for variation in cleavages. Selectivity The DUB families are selective in which ubiquitin chains they cleave. Not much is known about this selectively yet, but it has been shown that DUBs must structurally rearrange to conform to an active shape. Many DUBs are being linked to physiological roles as well as pathological, currently seen as a good drug target.