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Deconjugating Enzymes (DCEs)

Deconjugating enzymes (DCEs) can hydrolyse a peptide, amide, ester or thioester bond at the C-terminus of ubiquitin, including the post translationally formed isopeptide bonds found in mono-, multi-, and polyubiquitinylated conjugates. DCEs thus have the potential to regulate any ubiquitin/Ubl-mediated cellular process. Their conservation and widespread occurrence in eukaryotes, prokaryotes and viruses shows that these proteases constitute an essential class of enzymes.

Mammals contain some 80-90 deubiquitinylating enzymes (DUBs) falling into five subfamilies, namely the ubiquitin C-terminal hydrolases (UCHs); the ubiquitin-specific peptidases (USPs); the ovarian tumor (OTU) domain proteins; the Josephin or Machado-Joseph disease (MJD) proteins, and the JAMM (Jab1/MPN domain-associated metalloisopeptidase) domain proteases.

Most DUBs contain a catalytic domain that has sequence similarity within subfamilies and structural similarity across subfamilies, and unrelated sequences either N-terminal or C-terminal (or both) to the catalytic domain. These flanking sequences have been shown to mediate substrate binding and presumably serve as substrate binding domains in all DUBs. They, along with the catalytic core, could also contribute binding and cleavage specificity for different ubiquitin-ubiquitin isopeptide linkages.

Since most DUBs have been identified only by means of sequence similarity to catalytic motifs, there is little known functional information on many of these enzymes with only a handful of these DUBs having been characterized with respect to the proteins with which they interact and deubiquitinylate. However, it is becoming increasingly apparent that DUBs must acquire their substrates by binding the target protein in a conjugate or by associating with other macromolecular complexes. Further study may reveal a variety of protein partners including substrates, scaffolds, adaptors and ubiquitin receptors. Much of the regulation and specificity of deubiquitinylation arises from the association of DUBs with these protein partners.

The relatively few deconjugating enzymes characterized in detail to date provide insights into the crucial regulatory roles that they may play and making them potential drug target candidates for therapeutic intervention in ubiquitin/Ubl-related diseases.

 

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