Mechanism and Catalytic Site Atlas

Ubiquitin C-terminal hydrolase belongs to the peptidase C12 family and catalyses the hydrolysis of the peptide bond between the C-terminus of ubiquitin and either the epsilon amino group of a lysine residue or the alpha amino group of a protein. Ubiquitin is added enzymatically to the side-chains of lysine residues of acceptor proteins, with polyubiquination possible. The removal of the adducts is important for several reasons. Firstly, ubiquitin genes encode fusion proteins of either alpha-linked polyubiquitin or ubiquitin followed by a C-terminal peptide extension; in both cases proteolytic processing is required to generate ubiquitin monomers. Secondly, proteins are targeted for degradation by attachment of polyubiquitin chains: one ubiquitin molecule is linked to a lysine epsilon amino group of the protein to be targeted, a second ubiquitin is attached to a lysine residue of the first, and so on. Proteolytic processing is therefore required for release of polyubiquitin from the remnants of 26S proteasome substrates and for disassembly of polyubiquitin in order to recycle monomeric ubiquitin.

Ubiquitin C-terminal hydrolases (UCHs) constitute one of two main classes of de-ubiquitinating enzymes, the other being the UBPs (ubiquitin-specific proteases). In yeast UCH and UBP substrate specificities probably overlap, although the physiological substrates of UCH are unclear. Higher organisms can contain several different UCH enzymes, some of which are tissue specific and likely to target distinct substrates. UCHs are quite specific, cleaving only after the C-terminal glycine of ubiqutin.