ABSTRACT
Molecular cloning and DNA sequencing of a mammalian kidney and intestinal brush border membrane protease (EC 3.4.24.18) led to the discovery of the 'astacin family', a new family of metalloproteases. The family was named after a 200 amino acid crayfish endopeptidase called astacin, the first member of the group to be sequenced and crystallized. Thirty members have now been identified including meprins, bone morphogenetic protein-1 (BMP-1), and tolloid. The signature sequence for the family is: HEXXHXXGFXHEXXRXDR. Structural studies indicate these proteins bind zinc pentaco-ordinately, unlike thermolysin-like proteases, and bear relationships to serralysins, matrixins and snake venom metalloproteases. The protease domains of members of the astacin family share 18 to 98% amino acid identity, and have other domain similarities. For example, most members are synthesized with pre-and prosequences immediately NHrterminal to the protease domain. Several members contain one or two copies of epidermal growth factor (EGF)-like domains, and complement-like domains (Clr/Cls) near the COOHterminus. The pasting and patching of different domains to the protease domain create proteins of very different sizes and functions. The proteins of the family identified thus far are either bound to the plasma membrane or secreted from cells. They are expressed in a tissue-and species-specific manner in mature organisms, and in a temporal and spatial specific manner in developmental systems. They have been identified in a wide variety of species including bacteria, hydra, nematodes, fruit flies, frogs, fish, sea urchins, quail, mice, rats and humans. They are suggested to play roles in embryonic stages of development (in processes such as dorsal-ventral patterning, hatching, and eggshell matrix degradation), and in mature organisms (in processes such as cartilage and bone formation, fragmentation of peptide hormones or urinary proteins and in processes leading to extensive degradation). This chapter reviews the recent advances on the structure, function, regulation and evolution of the astacin family.
