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.
The availability of the human and mouse genome sequences has allowed the identification and comparison of their respective degradomes — the complete repertoire of proteases that are produced by these organisms. Because of the essential roles of proteolytic enzymes in the control of cell behaviour, survival and death, degradome analysis provides a useful framework for the global exploration of these protease-mediated functions in normal and pathological conditions.
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We thank all members of our laboratories for their comments on the manuscript and apologize for the omission of relevant works owing to space constraints. Our work is supported by grants from the Ministerio de Ciencia y Tecnología-Spain, the Gobierno del Principado de Asturias, Fundación 'La Caixa' and the European Union. C.M.O. is supported by a Canada Research Chair in Metalloproteinase Biology. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.
An intracellular protein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by ubiquitin.
A chemical group that can donate a pair of electrons in a chemical reaction.
- HIDDEN MARKOV MODEL
(HMM). A probabilistic model that is applied to protein and DNA sequence pattern recognition. HMMs represent a system as a set of discrete states and as transitions between those states. Each transition has an associated probability. HMMs are valuable because they allow a search or alignment algorithm to be built on firm probabilistic bases, and the parameters (transition probabilities) can be easily trained on a known data set.
Homologous genes that have originated as a result of a speciation event.
Homologous genes that have originated as a result of a duplication event.
Gene loci on the same chromosome. This term is often used to refer to gene loci in different organisms that are located on a chromosomal region of common evolutionary ancestry.
A database that provides a comprehensive catalogue and structure-based classification of proteases and inhibitors from a range of organisms.
A substrate-binding site that lies outside the catalytic domain of a protease and is located on specialized substrate-binding modules or domains.
The incorporation of DNA segments in a genome through a reverse-transcription-mediated mechanism.
A nutritionally and developmentally regulated process that is involved in the intracellular destruction of endogenous proteins and the removal of damaged organelles.
Chromosomal regions that contain groups of paralogous genes in the same order, which have presumably arisen by the duplication of large genomic fragments.
- SECRETORY GRANULE
A subcellular vesicle that contains molecules that are destined for secretion.
- MAST CELL
A specialized cell that initiates the inflammatory response by releasing histamine and other cytokines.
A serine protease that is produced by immune-system cells and stored in secretory granules.
A set of plasma proteins that form part of a proteolytic cascade, which leads to foreign-cell lysis and phagocytosis.
- PROSTATE INVOLUTION
A process by which the prostate gland reduces its size following androgen depletion.
- EXON SHUFFLING
The process of non-homologous recombination of exons from different genes.
A sequence of amino acids that precedes the catalytic domain in many inactive protease precursors. On removal or conformational change of the prodomain, the protease becomes active.
A protein that aids the folding of another to prevent it from taking an interactive conformation.
- SCISSILE BONDS
Peptide bonds that are cleaved by proteolytic enzymes.
A gene dosage effect that occurs when a diploid requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.
- LOSS OF HETEROZYGOSITY
A loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome missegregation.
A protease that is involved in the regulation of vascular tone
- BACTERIAL SEPSIS
Pathology that is caused by the spread of bacteria or their products through the bloodstream.
The time course of a drug and its metabolites in the body after administration.
- ECTODOMAIN SHEDDING
The protease-mediated release from the cell surface of the extracellular domain of integral membrane proteins.
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Puente, X., Sánchez, L., Overall, C. et al. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4, 544–558 (2003). https://doi.org/10.1038/nrg1111
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