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.

Metalloproteases are the most diverse of the four main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [1]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [2].

This entry contains proteins that belong to MEROPS peptidase family M24 (clan MG), which share a common structural-fold, the "pita-bread" fold. The fold contains both alpha helices and an anti-parallel beta sheet within two structurally similar domains that are thought to be derived from an ancient gene duplication. The active site, where conserved, is located between the two domains. The fold is common to methionine aminopeptidase (3.4.11.18), aminopeptidase P (3.4.11.9), prolidase (3.4.13.9), agropine synthase and creatinase (3.5.3.3). Though many of these peptidases require a divalent cation, creatinase is not a metal-dependent enzyme [2, 3, 4].

The entry also contains proteins that have lost catalytic activity, for example Spt16, which is a component of the FACT complex. The crystal structure of the N-terminal domain of Spt16, determined to 2.1A, reveals an aminopeptidase P fold whose enzymatic activity has been lost. This fold binds directly to histones H3-H4 through a interaction with their globular core domains, as well as with their N-terminal tails [5].

The FACT complex is a stable heterodimer in Saccharomyces cerevisiae (Baker's yeast) comprising Spt16p (P32558, IPR013953) and Pob3p (Q04636, IPR000969). The complex plays a role in transcription initiation and promotes binding of TATA-binding protein (TBP) to a TATA box in chromatin [6]; it also facilitates RNA Polymerase II transcription elongation through nucleosomes by destabilising and then reassembling nucleosome structure [7, 8, 9].

1. Evolutionary families of metallopeptidases. Meth. Enzymol. 248, 183-228
2. Sequence and structure comparison suggest that methionine aminopeptidase, prolidase, aminopeptidase P, and creatinase share a common fold. Proc. Natl. Acad. Sci. U.S.A. 91, 2473-7
3. Structure of creatine amidinohydrolase from Actinobacillus. Acta Crystallogr. D Biol. Crystallogr. 58, 1322-8
4. Structure of the cobalt-dependent methionine aminopeptidase from Escherichia coli: a new type of proteolytic enzyme. Biochemistry 32, 3907-12
5. The FACT Spt16 "peptidase" domain is a histone H3-H4 binding module. Proc. Natl. Acad. Sci. U.S.A. 105, 8884-9
6. The yeast FACT complex has a role in transcriptional initiation. Mol. Cell. Biol. 25, 5812-22
7. Defects in SPT16 or POB3 (yFACT) in Saccharomyces cerevisiae cause dependence on the Hir/Hpc pathway: polymerase passage may degrade chromatin structure. Genetics 162, 1557-71
8. FACT facilitates transcription-dependent nucleosome alteration. Science 301, 1090-3

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