Family C65
Summary for family C65
Family type peptidase | C65.001 - otubain-1 (Homo sapiens), MEROPS Accession MER0029056 (peptidase unit: 1-271) |
Content of family | Family C65 contains isopeptidases that release ubiquitin from polyubiquitin. |
History |
Identifier created: MEROPS 6.3 (23 June 2003) Ubiquitination of proteins is a cell-signalling mechanism in which ubiquitin is attached via its C-terminal glycine to amine groups on target proteins. Because one molecule of ubiquitin can attach to another ubiquitin molecule, target proteins can become polyubiquitinated; branched ubiquitin chains can form via an isopeptide bond involving Lys63. Ubiquitination is most frequently a signal for degradation, usually by the 26S proteasome (##XT01.002##). Removal of ubiquitin switches off the cell signal and also releases ubiquitin for recycling. There are a number of families containing peptidases that release ubiquitin, several of which are distant homologues of papain (C01.001). These include peptidases in families C12, C19, C64 and M67. The possibility that proteins in family C65 contained peptidases distantly related to papain was proposed by Makarova et al. 2000. Family C65 includes the product of the ovarian tumour gene OTU from Drosophila melanogaster, hence members of the family are called otubains. |
Catalytic type | Cysteine |
Active site residues | D88 C91 H265 |
Active site | The active site residues have been identified by site-directed mutagenesis (Balakirev et al., 2003). |
Activities and specificities | No physiological substrates have been identified for any members of the family. Otubain-1 (C65.001) has been shown to cleave tetra-ubiquitin at the isopeptide bond, but does not release ubiquitin from substrates of ubiquitin-specific peptidase 8 (C19.011), such as Leu-Arg-Gly-Gly-NHMec and ubiquitinated green fluorescent protein. |
Inhibitors | Ubiquitin aldehyde and the general cysteine peptidase inhibitor N-ethylmaleimide have been shown to inhibit otubain-1 (Balakirev et al., 2004). |
Molecular structure | The tertiary structure of otubain 2 (C65.002) has been determined, which shows that the fold is similar to that of papain (C01.001) (Nanao et al., 2004); hence family C65 is included in clan CA. Otubains-1 and -2 each have a nuclear localization signal at the N-terminus of the peptidase unit. The active site cysteine is followed by an ubiquitin-interaction motif (Xbb-Xaa-Ala-Xaa-Ser-Xaa-Xcc, in which Xaa is any amino acid, Xbb is an aromatic amino acid and Xcc is an acidic amino acid) and the consensus sequence Leu-Xaa-Xaa-Leu-Leu, which is known to mediate the binding of transcriptional co-activators to liganded nuclear receptors. Otubain-2 has a short, C-terminal extension which may function as an activator peptide because a form lacking this pentapeptide is active. Removal of the 47-residue N-terminal extension from otubain-1 does not affect its activity (Balakirev et al., 2004). |
Clan | CA |
Distribution of family
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