Human and mouse proteases: a comparative genomic approach

Proteolytic enzymes have fundamental roles in all living organisms. As well as nonspecific hydrolytic activities, proteases might also act as processing enzymes that perform highly selective and limited cleavage of specific substrates. These proteolytic processing events are essential in the control of cell behaviour, survival and death, and might be altered in many pathological conditions.The recent availability of the human and mouse genome sequences has opened the possibility of comparative and global analysis of their corresponding degradomes — the complete sets of proteases that are produced by these organisms.The human degradome consists of at least 553 proteases and homologues, which are distributed in five classes: 21 aspartic, 143 cysteine, 186 metallo, 176 serine and 27 threonine proteases. The mouse degradome is more complex, with at least 628 members — 514 being true orthologues of human proteases. This increased complexity mainly derives from the expansion of mouse protease families that are associated with reproductive and immunological functions.The evolution of both human and mouse degradomes has also been driven by the incorporation of a wide range of specialized functional modules to their catalytic domains. These ancillary domains are present in more than 40% of proteases, and act to modulate their interaction with substrates, inhibitors and receptors.Many proteases are linked to human disease owing to their overexpression in pathologies such as cancer, arthritis, neurodegenerative and cardiovascular diseases. However, we have also catalogued 53 hereditary degradomopathies that are caused mainly by loss-of-function mutations in protease genes. The generation of mouse models has provided valuable information on the molecular mechanisms that have a role in the development and progression of many diseases involving alterations in protease function.Molecular analysis of protease systems might facilitate the development of new strategies to treat diseases of proteolysis through target identification and the rational design of selective inhibitors for blocking overexpressed proteases or, alternatively, through methods that are aimed at replacing or increasing the activity of absent or defective proteases.