THE ASTACIN FAMILY OF METALLOENDOPEPTIDASES

The astacin family of metalloendopeptidases was recognized as a novel family of proteases in the 1990s. The crayfish enzyme astacin was the first characterized and is one of the smallest members of the family. More than 20 members of the family have now been identified. They have been detected in species ranging from hydra to humans, in mature and in developmental systems. Proposed functions of these proteases includ e activation Of growth factors, degradation of polypeptides, and proce ssing of extracellular proteins. Astacin family proteases are synthesi zed with NH2-terminal signal and proenzyme sequences, and many (such a s meprins, BMP-1, tolloid) contain multiple domains COOH-terminal to t he protease domain. They are either secreted from cells or are plasma membrane-associated enzymes. They have some distinguishing features in addition to the signature sequence in the protease domain: HEXXHXXGFX HEXXRXDR. They have a unique type of zinc binding, with pentacoordinat ion, and a protease domain tertiary structure that contains common att ributes with serralysins, matrix metalloendopeptidases, and snake veno m proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin and in proteins such as casein and gelatin; an d they have arylamidase activity. Meprins are unique proteases in the astacin family, and indeed in the animal kingdom, in their oligomeric structure; they are dimers of disulfide-linked dimers and are highly g lycosylated, type I integral membrane proteins that have many attribut es of receptors or integrins with adhesion, epidermal growth factor-li ke, and transmembrane domains. The alpha and beta subunits are differe ntially expressed and processed to yield latent and active proteases a s well as membrane-associated and secreted forms. Meprins represent ex cellent models of hetero- and homo-oligomeric enzymes that are regulat ed at the transcriptional and posttranslational levels.