PROSITE documentation PDOC51864

Astacin-like domain profile

Astacin or M12A [E1] family zinc metalloproteases are found in bacteria and animals. They belong to the metzincin protease family (see <PDOC00129>) and have diverse roles ranging from digestion of food to processing of extracellular matrix components. The first member of this family (astacin), a digestive enzyme, was identified in the freshwater crayfish Astacus astacus. In addition to astacin, other members of the astacin family proteases are involved in diverse biological functions such as dorsal/ventral determination in vertebrate and invertebrate (tolloid), morphogenesis in hydra (Hydra metalloproteinase-1), processing and degradation of peptides at the microvillar membrane of mammalian kidney and intestine (meprin), bone morphogenesis (bone morphogenetic protein 1, BMP1), inducing chorion hardening at the fertilization of medaka egg (alveolin), and digesting the egg envelope (chorion) at the time of hatching in teleostean (Hatching Enzyme 1, HE1). The minimal structure of an astacin protease is a catalytic domain of approximately 200 amino acid residues as found in bacteria. In eukaryotes, this minimal structure is extended by at least an N-terminal pro-peptide which confers latency, so that most astacins, including the prototypical crayfish enzyme, are secreted as inactive zymogens. Additional downstream domains include the EGF-like module (see <PDOC00021>), the CUB module (see <PDOC00908>), thrombospondin type-1 (TSP1) repeats (see <PDOC50092>), the ShK toxin domain (see <PDOC51670>) and the MATH/TRAF (see <PDOC50144>) and MAM (see <PDOC00604>) domains [1,2,3,4,5].

The mature astacin-like protease domain is composed of approximately 200 amino acid residues and is characterized by the consensus sequences HExxHxxGFxHExxRxDRD, the zinc-binding active site, and SxMHY, the methionine turn. In addition to these consensus sequences there are four conserved cysteine residues which are engaged in two intramolecular disulfide bonds (Cys1 connected to Cys4, and Cys2 to Cys3). In addition, selected members may show additionnal SS-bridges. Members of the hatching subgroup show a unique cross-link between two cysteine residues in the N-terminal segment of the astacin-like domain. The tolloid group shows a further unique bond between two consecutive residues of the upper-rim strand β4 enabled by a cis-peptide bond between them. The astacin-like domain has a mitten-like shape and consists of an upper N-terminal (NTS) and a lower C-terminal sub-domain (CTS), with a deep active-site cleft in between (see <PDB:3LQB>). The NTS consists mainly of two long α-helices, one centrally located and one more peripheral, and of a strongly twisted five-stranded β-sheet. The CTS consists of three 3(10)-helices, one α-helix, and a two-stranded anti-parallel β-sheet. The central cleft represents the active site of the domain that is crucial for substrate recognition and catalysis. The zinc ion, located at the bottom of this cleft, is pentacoordinated in a trigonal-bipyramidal geometry by the three histidine residues in the binding motif, the tyrosine in the methionine-turn and by a water molecule, which is also bound to the carboxylate side chain of the glutamate in the binding motif. The zinc atom acts as an electrophilic center to enhance the reactivity of a water molecule prior to nucleophilic attack on the carbonyl carbon of the scissile peptide bond [6,7,8].

The profile we developed covers the entire astacin-like domain.