A genomic analysis of rat proteases and protease inhibitors

Abstract

Proteases perform important roles in multiple biological and pathological processes. The availability of the rat genome sequence has facilitated the analysis of the complete protease repertoire or degradome of this model organism. The rat degradome consists of at least 626 proteases and homologs, which are distributed into 24 aspartic, 160 cysteine, 192 metallo, 221 serine, and 29 threonine proteases. This distribution is similar to that of the mouse degradome but is more complex than that of the human degradome composed of 561 proteases and homologs. This increased complexity of rat proteases mainly derives from the expansion of several families, including placental cathepsins, testases, kallikreins, and hematopoietic serine proteases, involved in reproductive or immunological functions. These protease families have also evolved differently in rat and mouse and may contribute to explain some functional differences between these closely related species. Likewise, genomic analysis of rat protease inhibitors has shown some differences with mouse protease inhibitors and the expansion of families of cysteine and serine protease inhibitors in rodents with respect to human. These comparative analyses may provide new views on the functional diversity of proteases and inhibitors and contribute to the development of innovative strategies for treating proteolysis diseases.

Figure 1

A global view of the rat degradome and comparison with those of mouse and human. The figure represents the complete set of proteases and protease–homologs from each species distributed into five catalytic classes. Proteases absent in one species are shown as black bars.

Figure 2

Unrooted phylogenetic tree of the C01 family of cysteine proteases. The testin subfamily of rodent-specific proteases is shown in red, and placental cathepsins, which are also rodent-specific, are shown in green. Branches corresponding to rat-specific members are shown in white; those mouse-specific, in red. Cathepsin L–like proteases, the only group containing one extra member in human, are shown in blue.

Figure 3

Phylogenetic tree of rat glandular kallikreins and comparison with those of mouse and human. The tree illustrates an independent expansion of rat and mouse glandular kallikreins. Rat-specific and mouse-specific glandular kallikreins are shown in red and in green, respectively. Human-specific kallikreins, including KLK2 and prostate specific antigen/KLK3, are shown in blue.

Figure 4

Comparison of rat hematopoietic serine proteases clustered at 15p13 with those of mouse at 14C1 and human at 14q11. Gene position and orientation are indicated by arrowheads; black ones represent genes, and red ones denote pseudogenes. Connecting lines indicate orthology or gene expansion.

Figure 5

Comparative analysis of a cluster of rat serpins at 17p12 with the corresponding region of human and mouse genomes. The order and orientation of genes are indicated by black arrowheads, and pseudogenes are represented by red arrowheads. Orthology is indicated by connecting lines.