In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:

• Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
• Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.

In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [1].

This group of proteins contain cysteine peptidases belonging to MEROPS peptidase family C48 (Ulp1 endopeptidase family, clan CE). The protein fold of the peptidase domain for members of this family resembles that of adenain, the type example for clan CE. This group of sequences also contains a number of hypothetical proteins, which have not yet been characterised, and non-peptidase homologues. These are proteins that have either been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity of the peptidases in the family.

The Ulp1 endopeptidase family contain the deubiquitinating enzymes (DUB) that can de-conjugate ubiquitin or ubiquitin-like proteins from ubiquitin-conjugated proteins. They can be classified in 3 families according to sequence homology [2, 3]: Ubiquitin carboxyl-terminal hydrolase (UCH) (see PDOC00127), Ubiquitin-specific processing protease (UBP) (see PDOC00750), and ubiquitin-like protease (ULP) specific for de-conjugating ubiquitin-like proteins. In contrast to the UBP pathway, which is very redundant (16 UBP enzymes in yeast), there are few ubiquitin-like proteases (only one in yeast, Ulp1).

Ulp1 catalyses two critical functions in the SUMO/Smt3 pathway via itscysteine protease activity. Ulp1 processes the Smt3 C-terminal sequence(-GGATY) to its mature form (-GG), and it de-conjugates Smt3 from the lysineepsilon-amino group of the target protein [4].

Crystal structure of yeast Ulp1 bound to Smt3 [5] revealed that the catalytic and interaction interface is situated in a shallow and narrow cleft where conserved residues recognise the Gly-Gly motif at the C-terminal extremity of Smt3 protein. Ulp1 adopts a novel architecture despite some structural similarity with other cysteine protease. The secondary structure is composed of seven alpha helices and seven beta strands. The catalytic domain includes the central alpha helix, beta-strands 4 to 6, and the catalytic triad (Cys-His-Asp). This profile is directed against the C-terminal part of ULP proteins that displays full proteolytic activity [6].

1. Evolutionary lines of cysteine peptidases. Biol. Chem. 382, 727-33
2. Deubiquitinating enzymes: their diversity and emerging roles. Biochem. Biophys. Res. Commun. 266, 633-40
3. Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30, 405-39
4. A new protease required for cell-cycle progression in yeast. Nature 398, 246-51
5. Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol. Cell 5, 865-76

In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. C
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