InterPro: IPR004106 Peptidase S9A, oligopeptidase, N-terminal beta-propeller

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-, 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; 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 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.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [1]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Over 20 families (denoted S1 - S66) of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence [1]. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [1].

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [1]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds [1]. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [1, 2].

This entry represents the beta-propeller domain found at the N-terminal of prolyl oligopeptidase, including acylamino-acid-releasing enzyme (also known as acylaminoacyl peptidase), which belong to the MEROPS peptidase family S9 (clan SC), subfamily S9A. The prolyl oligopeptidase family consist of a number of evolutionary related peptidases whose catalytic activity seems to be provided by a charge relay system similar to that of the trypsin family of serine proteases, but which evolved by independent convergent evolution. The N-terminal domain of prolyl oligopeptidases form an unusual 7-bladed beta-propeller consisting of seven 4-stranded beta-sheet motifs.

Prolyl oligopeptidase is a large cytosolic enzyme involved in the maturation and degradation of peptide hormones and neuropeptides, which relate to the induction of amnesia. The enzyme contains a peptidase domain, where its catalytic triad (Ser554, His680, Asp641) is covered by the central tunnel of the N-terminal beta-propeller domain. In this way, large structured peptides are excluded from the active site, thereby protecting larger peptides and proteins from proteolysis in the cytosol [3]. The protein fold of the peptidase domain for members of this family resembles that of serine carboxypeptidase D, the type example of clan SC. Mammalian acylaminoacyl peptidase is an exopeptidase that is a member of the same prolyl oligopeptidase family of serine peptidases. This enzyme removes acylated amino acid residues from the N terminus of oligopeptides [4].