Family C64

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

Summary for family C64

Family type peptidaseC64.001 - Cezanne peptidase (Homo sapiens), MEROPS Accession MER0029042 (peptidase unit: 167-413)
Content of familyFamily C64 contains endoisopeptidases that release ubiquitin from ubiquitinated proteins.
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: C12, C19, C65 and M67. The possibility that proteins in family C64 contained peptidases distantly related to papain was proposed by Makarova et al. 2000, and the peptidase activity was confirmed experimentally when Cezanne (C64.001) was shown to be a deubiquitinating enzyme (Evans et al., 2003).
Catalytic typeCysteine
Active site residuesC194 H358 
Active siteThe active site cysteine of Cezanne has been identified by site-directed mutagenesis (Evans et al., 2003). From the tertiary structure of tumor necrosis factor alpha-induced protein 3 (C64.003; Komander & Barford, 2008) Cys103 and His256 have been identified as catalytic residues. Asp70 has been suggested to be the third member of the active site triad, stabilizing His256. This is unusual amongst cysteine peptidases in clan CA where the residue that orientates the imidazolium ring is usually C-terminal of the histidine.
Activities and specificitiesCezanne has been shown to release ubiquitin from linear or branched synthetic ubiquitin chains and from ubiquitinated proteins (Evans et al., 2003). Cezanne-2 (C64.002) removes Lys63-linked ubiquitin chains from receptor interacting protein, a mediator of the proximal tumour necrosis factor receptor 1 signalling complex (Wertz et al., 2004).
Molecular structureThe tertiary structure of tumor necrosis factor alpha-induced protein 3 has been solved (Komander & Barford, 2008). The structure is similar to that of otubain-2 (C65.002). From the order of active site residues and sequence comparisons using Psi-Blast Makarova et al. 2000 family C64 is included in clan CA. The peptidase unit is in the N-terminal portion of the protein; in Cezanne-2, the C-terminus contains seven zinc fingers and a ubiquitin ligase domain.
ClanCA
Distribution of family Bacteria -  
Archaea -  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses -  
Biological functionsThe control of inflammation is partly brought about by the transcription factor NF-kappa B, which is located in the nucleus and induces genes that encode adhesion factors and chemokines. The mechanisms by which NF-kappa B is itself regulated are poorly understood, but Cezanne-2, a nuclear protein containing zinc finger domains, is known to be a negative regulator. Defective Cezanne-2 leads to chromic inflammation and cell death. Cezanne-2 binds to tumour-necrosis-factor-receptor-associated factors (TRAF). Cezanne-2 is a bifunctional molecule with the deubiquitinating enzyme at the N-terminus of the protein, and the C-terminal domain is a ubiquitin ligase by which receptor interacting protein (RIP) is ubiquitinated, leading to its degradation (Wertz et al., 2004). Cezanne and TRABID (C64.004) are cytoplasmically located and interact with TRAF6, and Cezanne has also been shown to down-regulate NF-kappa B (Evans et al., 2001).
Pharmaceutical and biotech relevanceMembers of family C64 are potential pharmaceutical targets because of their roles in controlling inflammation.
Statistics for family C64Sequences:1326
Identifiers:6
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
Cezanne peptidaseC64.001-
Cezanne-2 peptidaseC64.002Yes
A20 peptidaseC64.003Yes
trabid peptidaseC64.004Yes
VCIP135 deubiquitinating peptidaseC64.006-
Y50C1A.1 protein (Caenorhabditis elegans)C64.A01-
family C64 non-peptidase homologuesnon-peptidase homologue-
family C64 unassigned peptidasesunassignedYes