The Degradome database: mammalian proteases and diseases of proteolysis

Abstract

The degradome is defined as the complete set of proteases present in an organism. The recent availability of whole genomic sequences from multiple organisms has led us to predict the contents of the degradomes of several mammalian species. To ensure the fidelity of these predictions, our methods have included manual curation of individual sequences and, when necessary, direct cloning and sequencing experiments. The results of these studies in human, chimpanzee, mouse and rat have been incorporated into the Degradome database, which can be accessed through a web interface at http://degradome.uniovi.es. The annotations about each individual protease can be retrieved by browsing catalytic classes and families or by searching specific terms. This web site also provides detailed information about genetic diseases of proteolysis, a growing field of great importance for multiple users. Finally, the user can find additional information about protease structures, protease inhibitors, ancillary domains of proteases and differences between mammalian degradomes.

Figure 1.

Main features of the Degradome database. (A) Individual annotations of aspartyl proteases. The first column contains the name of the family, with a hyperlink to a web page where the user can find related selected publications and structures. The second column contains the name of each protease, with a hyperlink which opens a ‘popup’ table with further general information—in this example, ‘presenilin 1’. The rest of the columns show the symbol of each protease in each organism, with a hyperlink which opens a ‘popup’ table with species-specific information—in this example, ‘human presenilin 1’. Pseudogenes are shown over a ‘pink background’. Proteases absent in a species are shown as ‘empty grey cells’. (B) Search interface. ‘Dropdown boxes’ are used to define the query. In this example, 26 proteases have been found to contain the term ‘mmp’ in any field of any species. The ‘yellow boxes’ have been added to show additional possibilities for each field of the query definition. The search is case-insensitive by default, but an ‘option box’ exists to make the search case-sensitive. Searches can be combined by ‘keeping’ results from a previous search, ‘adding’ results to a previous search or ‘removing’ results from a previous search. (C) Mutated proteases in human hereditary diseases. Each row contains information about gene locus, disease name, OMIM entry, mode of inheritance, pathologic protease alteration (activity gain or loss), and availability of animal models containing the same protease anomaly. (D) Interactive structure representation of ‘thimet oligopeptidase’, from the M03 metalloprotease family. The structure can be rotated, moved, and zoomed. A ‘discontinuous bar’ shows the coordination of the catalytic water molecule with the zinc ion (‘golden sphere’). An ‘arrow’ shows the electrostatic interaction between the catalytic glutamic acid side chain and the catalytic water molecule.