DAP abstract: Difference between revisions

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Peptidases are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry. 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.
As a member of the MH clan in the M18 family of zinc metallopeptidase 2 molecules Aspartyl aminopeptidase is part of the basic protein degrading machinery of the cell. It cleaves Glutamyl or Aspartyl residues from the unblocked N-terminus of the cell and is distinct from Glu aminopeptidase by having a preference for Asp residues. This protein in ''Peudomonas Aeruginosa'' has a dodecameric tetrahedral structure similar to that of glutamyl aminopeptidase in ''Pyrococcus horikoshii''. It cleaves unblocked residues by allowing only unfolded proteins to pass through channels in the face of the tetrahedral structure to interact with the zinc catalytic centre. This protein has a high sequence conservation between broad classes of organisms, evolution mechanism is considered to be laterally transferred and is expressed at fairly even levels throughout mammalian tissues >0.1% confirming its importance as a basic metabolic cellular protein.
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.
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. 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.
This group of metallopeptidases belong to the MEROPS peptidase family M18, (clan MH). The proteins have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His. The catalysed reaction involves the release of an N-terminal aminoacid, usually neutral or hydrophobic, from a polypeptide.
The type example is aminopeptidase I from Saccharomyces cerevisiae, the sequence of which has been deduced, and the mature protein shown to consist of 469 amino acids. A 45-residue presequence contains both positively- and negatively-charged and hydrophobic residues, which could be arranged in an N-terminal amphiphilic alpha-helix. The presequence differs from signal sequences that direct proteins across bacterial plasma membranes and endoplasmic reticulum or into mitochondria. It is unclear how this unique presequence targets aminopeptidase I to yeast vacuoles, and how this sorting utilises classical protein secretory pathways

Latest revision as of 06:33, 8 June 2008

As a member of the MH clan in the M18 family of zinc metallopeptidase 2 molecules Aspartyl aminopeptidase is part of the basic protein degrading machinery of the cell. It cleaves Glutamyl or Aspartyl residues from the unblocked N-terminus of the cell and is distinct from Glu aminopeptidase by having a preference for Asp residues. This protein in Peudomonas Aeruginosa has a dodecameric tetrahedral structure similar to that of glutamyl aminopeptidase in Pyrococcus horikoshii. It cleaves unblocked residues by allowing only unfolded proteins to pass through channels in the face of the tetrahedral structure to interact with the zinc catalytic centre. This protein has a high sequence conservation between broad classes of organisms, evolution mechanism is considered to be laterally transferred and is expressed at fairly even levels throughout mammalian tissues >0.1% confirming its importance as a basic metabolic cellular protein.

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