Family C67
Summary for family C67
| Family type peptidase | C67.001 - CylD peptidase (Homo sapiens), MEROPS Accession MER0030104 (peptidase unit: 593-894) |
| Content of family | Peptidase family C67 contain endopeptidases that release ubiquitin from polyubiquitinated proteins. |
| History |
Identifier created: MEROPS 6.4 (24 September 2003)
When the protein ubiquitin is attached to a protein, the tagged protein can become a target for degradation by the proteasome (##XT01.001##). Ubiquitin itself can then become ubiquitinated via the amide on Lys48, so that branched-chain multiubiquitin adducts form and the tagged protein becomes poly-ubiquitinated. There are several families of cysteine endopeptidases (see C12, C19) that release ubiquitin from poly-ubiquitinated proteins prior to degradation. However, some proteins require poly-ubiquitination to be in the active form. One such protein is TRAF2, which is involved in the NF-κB cell-signalling pathway. Family C67 includes the CylD protein (C67.001), which has been shown to release ubiquitin from TRAF2. |
| Catalytic type | Cysteine |
| Active site residues | Q595 C601 H871 D889 |
| Active site | The active site residues have been identified from the tertiary structure to be Gln595, Cys601, His871 and Asp889 (Komander et al., 2008. |
| Activities and specificities | CylD has de-ubiquitinating activity that is directed towards non-Lys48-linked polyubiquitin chains (Kovalenko et al., 2003). |
| Molecular structure | The tertiary structure of the peptidase unit (also knonw as the USP domain) has been solved and shows a papain-like fold (Komander et al., 2008), hence family C67 is included in clan CA. However, the USP domain is organized into four subdomains, unlike other deubiquitinating enzymes. |
| Clan | CA |
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Distribution of family
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Bacteria |
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Archaea |
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Protozoa |
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Fungi |
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Plants |
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Animals |
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Viruses |
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| Biological functions | The transcription factor NF-κB is involved in inflammation, immune responses and protection against apoptosis. It is present in the cytoplasm in an inactive state bound to its inhibitor IκB. Following a cell signalling event, which can be mediated by TRAF2, IκB is phosphorylated by the IκB kinase complex, and degraded by the proteasome (##XT01.001##). This allows NF-κB to locate to the nucleus where it activates its target genes. CylD affects this pathway in two ways. It binds to the NEMO component of the IκB kinase complex, which leads to complex degradation, and it inactivates TRAF2 by de-ubiquitination (Kovalenko et al., 2003, Brummelkamp et al., 2003). |
| Pharmaceutical and biotech relevance | Familial cylindromatosis ('turban tumour syndrome'), characterized by multiple neoplasms of the skin appendages, has been localized to the CYLD gene (Takahashi et al., 2000). The CYLD gene is truncated leading to loss of enzyme activity (Trompouki et al., 2003). |
| Statistics for family C67 | Sequences: | 512 |
| Identifiers: | 4 |
| Identifiers with PDB entries: | 2 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
