Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Human and mouse proteases: a comparative genomic approach

Key Points

  • 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.

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The protease wheel.
Figure 2: Ancillary domains present in human and mouse proteases.

References

  1. 1

    Barrett, A. J., Rawlings, N. D. & Woessner, J. F. Handbook of Proteolytic Enzymes (Academic Press, San Diego, 1998). An essential book in the protease field that comprehensively lists and describes proteases from many organisms.

    Google Scholar 

  2. 2

    Hooper, N. M. Proteases in Biology and Medicine (Portland Press, London, 2002).

    Google Scholar 

  3. 3

    Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002). This review illustrates the diversity of protease functions in pathological processes such as cancer.

    CAS  Google Scholar 

  4. 4

    Krane, S. M. Elucidation of the potential roles of matrix metalloproteinases in skeletal biology. Arthritis Res. Ther. 5, 2–4 (2003).

    CAS  PubMed  Google Scholar 

  5. 5

    Esler, W. P. & Wolfe, M. S. A portrait of Alzheimer secretases — new features and familiar faces. Science 293, 1449–1454 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Luttun, A., Dewerchin, M., Collen, D. & Carmeliet, P. The role of proteinases in angiogenesis, heart development, restenosis, atherosclerosis, myocardial ischemia, and stroke: insights from genetic studies. Curr. Atheroscler. Rep. 2, 407–416 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Uría, J. A. & López-Otín, C. Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. Cancer Res. 60, 4745–4751 (2000).

    PubMed  Google Scholar 

  8. 8

    Geier, E. et al. A giant protease with potential to substitute for some functions of the proteasome. Science 283, 978–981 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    Voges, D., Zwickl, P. & Baumeister, W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu. Rev. Biochem. 68, 1015–1068 (1999).

    CAS  Google Scholar 

  10. 10

    López-Otín, C. & Overall, C. M. Protease degradomics: a new challenge for proteomics. Nature Rev. Mol. Cell Biol. 3, 509–519 (2002). This article introduces new concepts and approaches for the global analysis of proteases in normal and pathological conditions, and especially in cancer.

    Google Scholar 

  11. 11

    Rawlings, N. D., O'Brien, E. & Barrett, A. J. MEROPS: the protease database. Nucleic Acids Res. 30, 343–346 (2002). A description of a database that is freely available to the academic community, which represents an essential resource for research on proteases.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  13. 13

    Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Zucker, S. & Chen, W. -T. Cell Surface Proteases (Academic Press, San Diego, 2003). A compilation of articles that cover recent advances in the functional analysis of membrane-bound proteases, which are a group of enzymes that are of growing relevance in normal and pathological conditions.

    Google Scholar 

  15. 15

    Cope, G. A. et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298, 608–611 (2002).

    CAS  PubMed  Google Scholar 

  16. 16

    Urban, S., Lee, J. R. & Freeman, M. A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands. EMBO J. 21, 4277–4286 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Mariño, G. et al. Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy. J. Biol. Chem. 278, 3671–3678 (2003).

    PubMed  Google Scholar 

  18. 18

    Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K. & Martoglio, B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215–2218 (2002).

    CAS  PubMed  Google Scholar 

  19. 19

    Makarova, K. S., Aravind, L. & Koonin, E. V. A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae. Trends Biochem. Sci. 25, 50–52 (2000).

    CAS  Google Scholar 

  20. 20

    Krylov, D. M. & Koonin, E. V. A novel family of predicted retroviral-like aspartyl proteases with a possible key role in eukaryotic cell cycle control. Curr. Biol. 11, 584–587 (2001).

    Google Scholar 

  21. 21

    Mouse Genome Sequence Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

  22. 22

    Swanson, W. J. & Vacquier, V. D. The rapid evolution of reproductive proteins. Nature Rev. Genet. 3, 137–144 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Balbín, M. et al. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J. Biol. Chem. 276, 10253–10262 (2001).

    PubMed  Google Scholar 

  24. 24

    Deussing, J. et al. Identification and characterization of a dense cluster of placenta-specific cysteine peptidase genes and related genes on mouse chromosome 13. Genomics 79, 225–240 (2002).

    CAS  PubMed  Google Scholar 

  25. 25

    Sol-Church, K. et al. Evolution of placentally expressed cathepsins. Biochem. Biophys. Res. Commun. 293, 23–29 (2002).

    CAS  PubMed  Google Scholar 

  26. 26

    Yeh, E. T., Gong, L. & Kamitani, T. Ubiquitin-like proteins: new wines in new bottles. Gene 248, 1–14 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

    Brachvogel, B. et al. Molecular cloning and expression analysis of a novel member of the disintegrin and metalloprotease-domain (ADAM) family. Gene 288, 203–210 (2002).

    CAS  PubMed  Google Scholar 

  28. 28

    Olsson, A. Y. & Lundwall, A. Organization and evolution of the glandular kallikrein locus in Mus musculus. Biochem. Biophys. Res. Commun. 299, 305–311 (2002).

    PubMed  Google Scholar 

  29. 29

    Yousef, G. M. & Diamandis, E. P. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr. Rev. 22, 184–204 (2001).

    CAS  Google Scholar 

  30. 30

    Luo, L. Y. et al. The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res. 63, 807–811 (2003).

    CAS  PubMed  Google Scholar 

  31. 31

    Balk, S. P., Ko, Y. J. & Bubley, G. J. Biology of prostate-specific antigen. J. Clin. Oncol. 21, 383–391 (2003).

    CAS  PubMed  Google Scholar 

  32. 32

    Caputo, E., Manco, G., Mandrich, L. & Guardiola, J. A novel aspartyl proteinase from apocrine epithelia and breast tumors. J. Biol. Chem. 275, 7935–7941 (2000).

    CAS  PubMed  Google Scholar 

  33. 33

    Yoshida, M., Kaneko, M., Kurachi, H. & Osawa, M. Identification of two rodent genes encoding homologues to seminal vesicle autoantigen: a gene family including the gene for prolactin-inducible protein. Biochem. Biophys. Res. Commun. 281, 94–100 (2001).

    CAS  PubMed  Google Scholar 

  34. 34

    Lunderius, C. & Hellman, L. Characterization of the gene encoding mouse mast cell protease 8 (mMCP-8), and a comparative analysis of hematopoietic serine protease genes. Immunogenetics 53, 225–232 (2001).

    CAS  PubMed  Google Scholar 

  35. 35

    Garnier, G., Circolo, A., Xu, Y. & Volanakis, J. E. Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system. Biochem. J. 371, 631–640 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Nishimura, H. et al. The ADAM1a and ADAM1b genes, instead of the ADAM1 (fertilin-α) gene, are localized on mouse chromosome 5. Gene 291, 67–76 (2002).

    CAS  PubMed  Google Scholar 

  37. 37

    Grima, J., Wong, C. C., Zhu, L. J., Zong, S. D. & Cheng, C. Y. Testin secreted by Sertoli cells is associated with the cell surface, and its expression correlates with the disruption of Sertoli-germ cell junctions but not the inter-Sertoli tight junction. J. Biol. Chem. 273, 21040–21053 (1998).

    CAS  PubMed  Google Scholar 

  38. 38

    Fischer, H., Koenig, U., Eckhart, L. & Tschachler, E. Human caspase 12 has acquired deleterious mutations. Biochem. Biophys. Res. Commun. 293, 722–726 (2002).

    CAS  Google Scholar 

  39. 39

    Grzmil, P. et al. Human cyritestin genes (CYRN1 and CYRN2) are non-functional. Biochem. J. 357, 551–556 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    O'Sullivan, C. M., Liu, S. Y., Karpinka, J. B. & Rancourt, D. E. Embryonic hatching enzyme strypsin/ISP1 is expressed with ISP2 in endometrial glands during implantation. Mol. Reprod. Dev. 62, 328–334 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Kageyama, T. Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development. Cell. Mol. Life Sci. 59, 288–306 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Rose, S. D. & MacDonald, R. J. Evolutionary silencing of the human elastase I gene (ELA1). Hum. Mol. Genet. 6, 897–903 (1997).

    CAS  PubMed  Google Scholar 

  43. 43

    Suzuki, H. & Kumagai, H. Autocatalytic processing of γ-glutamyltranspeptidase. J. Biol. Chem. 277, 43536–43543 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    Paulding, C. A., Ruvolo, M. & Haber, D. A. The Tre2 (USP6) oncogene is a hominoid-specific gene. Proc. Natl Acad. Sci. USA 100, 2507–2511 (2003).

    CAS  PubMed  Google Scholar 

  45. 45

    Fougerousse, F. et al. Human–mouse differences in the embryonic expression patterns of developmental control genes and disease genes. Hum. Mol. Genet. 9, 165–173 (2000).

    CAS  PubMed  Google Scholar 

  46. 46

    Emes, R. D., Goodstadt, L., Winter, E. E. & Ponting, C. P. Comparison of the genomes of human and mouse lays the foundation of genome zoology. Hum. Mol. Genet. 12, 701–709 (2003). An excellent analysis of the differences among human and mouse genomes and discussion of their physiological relevance.

    CAS  Google Scholar 

  47. 47

    Salamonsen, L. A. & Nie, G. Proteases at the endometrial–trophoblast interface: their role in implantation. Rev. Endocr. Metab. Disord. 3, 133–143 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Fata, J. E., Ho, A. T., Leco, K. J., Moorehead, R. A. & Khokha, R. Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors. Cell. Mol. Life Sci. 57, 77–95 (2000).

    CAS  PubMed  Google Scholar 

  49. 49

    Curry, T. E. & Osteen, K. G. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol. Reprod. 64, 1285–1296 (2001).

    CAS  PubMed  Google Scholar 

  50. 50

    Evans, J. P. Fertilin-β and other ADAMs as integrin ligands: insights into cell adhesion and fertilization. Bioessays 23, 628–639 (2001).

    CAS  PubMed  Google Scholar 

  51. 51

    Seals, D. F. & Courtneidge, S. A. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 17, 7–30 (2003).

    CAS  PubMed  Google Scholar 

  52. 52

    Ny, T., Wahlberg, P. & Brandstrom, I. J. Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems. Mol. Cell Endocrinol. 187, 29–38 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Hulboy, D. L., Rudolph, L. A. & Matrisian, L. M. Matrix metalloproteinases as mediators of reproductive function. Mol. Hum. Reprod. 3, 27–45 (1997).

    CAS  PubMed  Google Scholar 

  54. 54

    Vu, T. H. & Werb, Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 14, 2123–2133 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Overall, C. M. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol. Biotechnol. 22, 51–86 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Mahon, P. & Bateman, A. The PA domain: a protease-associated domain. Protein Sci. 9, 1930–1934 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Luo, X. & Hofmann, K. The protease-associated domain: a homology domain associated with multiple classes of proteases. Trends Biochem. Sci. 26, 147–148 (2001).

    CAS  PubMed  Google Scholar 

  58. 58

    Llamazares, M., Cal, S., Quesada, V. & López-Otín, C. Identification and characterization of ADAMTS-20 defines a novel subfamily of metalloproteinases-disintegrins with multiple thrombospondin-1 repeats and a unique GON-domain. J. Biol. Chem. 278, 13382–13389 (2003).

    CAS  PubMed  Google Scholar 

  59. 59

    Somerville, R. P. et al. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J. Biol. Chem. 278, 9503–9513 (2003).

    CAS  PubMed  Google Scholar 

  60. 60

    Hooper, J. D., Clements, J. A., Quigley, J. P. & Antalis, T. M. Type II transmembrane serine proteases: insights into an emerging class of cell surface proteolytic enzymes. J. Biol. Chem. 276, 857–860 (2001).

    CAS  Google Scholar 

  61. 61

    Velasco, G., Cal, S., Quesada, V., Sanchez, L. M. & Lopez-Otin, C. Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J. Biol. Chem. 277, 37637–37646 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Wex, T., Wex, H. & Bromme, D. The human cathepsin F gene — a fusion product between an ancestral cathepsin and cystatin gene. Biol. Chem. 380, 1439–1442 (1999).

    CAS  PubMed  Google Scholar 

  63. 63

    Nagler, D. K., Sulea, T. & Menard, R. Full-length cDNA of human cathepsin F predicts the presence of a cystatin domain at the N-terminus of the cysteine protease zymogen. Biochem. Biophys. Res. Commun. 257, 313–318 (1999).

    CAS  PubMed  Google Scholar 

  64. 64

    McQuibban, G. A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Tam, E. M., Wu, Y. I., Butler, G. S., Stack, M. S. & Overall, C. M. Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1–MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1MMP inhibits cell invasion by disrupting native type I collagen cleavage. J. Biol. Chem. 277, 39005–39014 (2002).

    CAS  PubMed  Google Scholar 

  66. 66

    Ehlers, M. R., Fox, E. A., Strydom, D. J. & Riordan, J. F. Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc. Natl Acad. Sci. USA 86, 7741–7745 (1989).

    CAS  Google Scholar 

  67. 67

    Azuma, T., Liu, W. G., Vander Laan, D. J., Bowcock, A. M. & Taggart, R. T. Human gastric cathepsin E gene. Multiple transcripts result from alternative polyadenylation of the primary transcripts of a single gene locus at 1q31–q32. J. Biol. Chem. 267, 1609–1614 (1992).

    CAS  PubMed  Google Scholar 

  68. 68

    Freije, J. M. et al. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269, 16766–16773 (1994).

    CAS  PubMed  Google Scholar 

  69. 69

    Heuze-Vourc'h, N., Leblond, V. & Courty, Y. Complex alternative splicing of the hKLK3 gene coding for the tumor marker PSA (prostate-specific-antigen). Eur. J. Biochem. 270, 706–714 (2003).

    CAS  PubMed  Google Scholar 

  70. 70

    Rieder, M. J., Taylor, S. L., Clark, A. G. & Nickerson, D. A. Sequence variation in the human angiotensin converting enzyme. Nature Genet. 22, 59–62 (1999).

    CAS  PubMed  Google Scholar 

  71. 71

    Williams, A. G. et al. The ACE gene and muscle performance. Nature 403, 614 (2000).

    CAS  PubMed  Google Scholar 

  72. 72

    Niu, T., Chen, X. & Xu, X. Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications. Drugs 62, 977–993 (2002).

    CAS  PubMed  Google Scholar 

  73. 73

    Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002). Together with reference 74, this paper illustrates the increased susceptibility to common diseases that is associated with genetic variation in some protease genes.

    CAS  PubMed  Google Scholar 

  74. 74

    Horikawa, Y. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26, 163–175 (2000).

    CAS  PubMed  Google Scholar 

  75. 75

    Devlin, A. M. et al. Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia. Hum. Mol. Genet. 9, 2837–2844 (2000).

    CAS  PubMed  Google Scholar 

  76. 76

    Yamada, Y. et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N. Engl. J. Med. 347, 1916–1923 (2002).

    CAS  PubMed  Google Scholar 

  77. 77

    Murphy, G. et al. Matrix metalloproteinases in arthritic disease. Arthritis Res. 4 (Suppl.) 39–49 (2002).

    Google Scholar 

  78. 78

    Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neurosci. 2, 502–511 (2001).

    CAS  Google Scholar 

  79. 79

    Brinckerhoff, C. E. & Matrisian, L. M. Matrix metalloproteinases: a tail of a frog that became a prince. Nature Rev. Mol. Cell Biol. 3, 207–214 (2002).

    CAS  Google Scholar 

  80. 80

    Parks, W. C. & Shapiro, S. D. Matrix metalloproteinases in lung biology. Respir. Res. 2, 10–19 (2001).

    CAS  PubMed  Google Scholar 

  81. 81

    Lomas, D. A. & Carrell, R. W. Serpinopathies and the conformational dementias. Nature Rev. Genet. 3, 759–768 (2002).

    CAS  PubMed  Google Scholar 

  82. 82

    Carrell, R. W. & Lomas, D. A. α1-antitrypsin deficiency — a model for conformational diseases. N. Engl. J. Med. 346, 45–53 (2002).

    CAS  PubMed  Google Scholar 

  83. 83

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    CAS  PubMed  Google Scholar 

  84. 84

    Bowen, D. J. Haemophilia A and haemophilia B: molecular insights. Mol. Pathol. 55, 1–18 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Hauri, H. P., Kappeler, F., Andersson, H. & Appenzeller, C. ERGIC-53 and traffic in the secretory pathway. J. Cell. Sci. 113, 587–596 (2000).

    CAS  PubMed  Google Scholar 

  86. 86

    Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nature Genet. 25, 160–165 (2000).

    CAS  PubMed  Google Scholar 

  87. 87

    Wang, J. et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98, 47–58 (1999).

    CAS  Google Scholar 

  88. 88

    Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).

    CAS  PubMed  Google Scholar 

  89. 89

    Huang, Y. & Wang, K. K. The calpain family and human disease. Trends Mol. Med. 7, 355–362 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Levy, G. G. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413, 488–494 (2001).

    CAS  PubMed  Google Scholar 

  91. 91

    Guipponi, M. et al. The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum. Mol. Genet. 11, 2829–2836 (2002).

    CAS  PubMed  Google Scholar 

  92. 92

    Citron, M. et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Gehring, N. H. et al. Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nature Genet. 28, 389–392 (2001).

    CAS  PubMed  Google Scholar 

  94. 94

    De Jonghe, C. et al. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Aβ42 secretion. Hum. Mol. Genet. 8, 1529–1540 (1999).

    CAS  PubMed  Google Scholar 

  95. 95

    Molinari, F. et al. Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science 298, 1779–1781 (2002).

    CAS  PubMed  Google Scholar 

  96. 96

    Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    CAS  PubMed  Google Scholar 

  97. 97

    Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002).

    CAS  PubMed  Google Scholar 

  98. 98

    Belaaouaj, A. et al. Mice lacking neutrophil elastase reveal impaired host defense against Gram negative bacterial sepsis. Nature Med. 4, 615–618 (1998).

    CAS  PubMed  Google Scholar 

  99. 99

    Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G. & Dale, D. C. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature Genet. 23, 433–436 (1999).

    CAS  PubMed  Google Scholar 

  100. 100

    Pendás, A. M. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nature Genet. 31, 94–99 (2002). Together with references 101 and 102, this paper is an example of the usefulness of mouse models and genetic approaches to identify the in vivo substrates of proteases.

    PubMed  Google Scholar 

  101. 101

    Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).

    CAS  PubMed  Google Scholar 

  103. 103

    Ranger, A. M., Malynn, B. A. & Korsmeyer, S. J. Mouse models of cell death. Nature Genet. 28, 113–118 (2001).

    CAS  PubMed  Google Scholar 

  104. 104

    Rakic, J. M. et al. Role of plasminogen activator-plasmin system in tumor angiogenesis. Cell Mol. Life Sci. 60, 463–473 (2003).

    CAS  PubMed  Google Scholar 

  105. 105

    Lund, L. R. et al. Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J. 18, 4645–4656 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator. Nature Rev. Mol. Cell Biol. 3, 932–943 (2002).

    CAS  Google Scholar 

  107. 107

    Holmbeck, K. et al. MT1–MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999).

    CAS  PubMed  Google Scholar 

  108. 108

    Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000).

    CAS  PubMed  Google Scholar 

  109. 109

    Caterina, J. J. et al. Enamelysin (matrix metalloproteinase 20)-deficient mice display an amelogenesis imperfecta phenotype. J. Biol. Chem. 277, 49598–49604 (2002).

    CAS  PubMed  Google Scholar 

  110. 110

    Coussens, L. M., Shapiro, S. D., Soloway, P. D. & Werb, Z. Models for gain-of-function and loss-of-function of MMPs: transgenic and gene targeted mice. Methods Mol. Biol. 151, 149–179 (2001).

    CAS  PubMed  Google Scholar 

  111. 111

    Wilson, S. M. et al. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nature Genet. 32, 420–425 (2002). An interesting example of a mouse disease that is caused by a mutation in a protease gene, the human orthologue of which has not yet been linked to an equivalent disorder.

    CAS  PubMed  Google Scholar 

  112. 112

    Neuhold, L. A. et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J. Clin. Invest. 107, 35–44 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Yu, Y. & Bradley, A. Engineering chromosomal rearrangements in mice. Nature Rev. Genet. 2, 780–790 (2001).

    CAS  PubMed  Google Scholar 

  114. 114

    Stanford, W. L., Cohn, J. B. & Cordes, S. P. Gene-trap mutagenesis: past, present and beyond. Nature Rev. Genet. 2, 756–768 (2001).

    CAS  PubMed  Google Scholar 

  115. 115

    Southan, C. A genomic perspective on human proteases as drug targets. Drug Discov. Today 6, 681–688 (2001). A discussion of the relevance of proteases as therapeutic targets.

    CAS  PubMed  Google Scholar 

  116. 116

    Overall, C. M. & López-Otín, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2, 657–672 (2002).

    CAS  Google Scholar 

  117. 117

    Soto, C. Protein misfolding and disease; protein refolding and therapy. FEBS Lett. 498, 204–207 (2001).

    CAS  Google Scholar 

  118. 118

    Crowther, D. C. Familial conformational diseases and dementias. Hum. Mutat. 20, 1–14 (2002).

    CAS  PubMed  Google Scholar 

  119. 119

    Cushman, D. W. & Ondetti, M. A. Design of angiotensin converting enzyme inhibitors. Nature Med. 5, 1110–1113 (1999). Together with reference 120, this article represents an example of the successful introduction of protease inhibitors to treat human disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Menendez-Arias, L. Targeting HIV: antiretroviral therapy and development of drug resistance. Trends Pharmacol. Sci. 23, 381–388 (2002).

    CAS  PubMed  Google Scholar 

  121. 121

    Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002). An excellent analysis of the lack of success of most MMP inhibitors developed for treating cancer and discussion of alternatives for future improvement in this field.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Gomis-Ruth, F. X. et al. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 389, 77–81 (1997).

    CAS  PubMed  Google Scholar 

  123. 123

    Bode, W. & Huber, R. Structural basis of the endoproteinase-protein inhibitor interaction. Biochim. Biophys. Acta 1477, 241–252 (2000).

    CAS  Google Scholar 

  124. 124

    Vendrell, J., Querol, E. & Aviles, F. X. Metallocarboxypeptidases and their protein inhibitors: structure, function and biomedical properties. Biochim. Biophys. Acta 1477, 284–298 (2000).

    CAS  PubMed  Google Scholar 

  125. 125

    Morgunova, E., Tuuttila, A., Bergmann, U. & Tryggvason, K. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc. Natl Acad. Sci. USA 99, 7414–7419 (2002).

    CAS  PubMed  Google Scholar 

  126. 126

    Turk, V., Turk, B. & Turk, D. Lysosomal cysteine proteases: facts and opportunities. EMBO J. 20, 4629–4633 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Anel, R. L. & Kumar, A. Experimental and emerging therapies for sepsis and septic shock. Expert Opin. Investig. Drugs 10, 1471–1485 (2001).

    CAS  PubMed  Google Scholar 

  128. 128

    Desnick, R. J. & Schuchman, E. H. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nature Rev. Genet. 3, 954–966 (2002). A comprehensive review that discusses the successes and shortcomings of present strategies to treat inherited metabolic disorders.

    CAS  PubMed  Google Scholar 

  129. 129

    Roth, D. A. et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 98, 3600–3606 (2001).

    CAS  PubMed  Google Scholar 

  130. 130

    Selkoe, D. J. Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease. J. Clin. Invest. 110, 1375–1381 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Kay, M. A. et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet. 24, 257–261 (2000).

    CAS  Google Scholar 

  132. 132

    Olson, M. V. & Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nature Rev. Genet. 4, 20–28 (2003). An excellent analysis of the relevance of comparative genomics and discussion of the argument that gene loss might be an important mechanism of rapid evolutionary change.

    CAS  Google Scholar 

  133. 133

    Kheradmand, F. & Werb, Z. Shedding light on sheddases: role in growth and development. Bioessays 24, 8–12 (2002). Together with reference 134, this review describes the functional relevance of the protease-mediated process of ectodomain shedding of membrane proteins.

    CAS  PubMed  Google Scholar 

  134. 134

    Arribas, J. & Borroto, A. Protein ectodomain shedding. Chem. Rev. 102, 4627–4638 (2002).

    CAS  PubMed  Google Scholar 

  135. 135

    Rudner, D. Z., Fawcett, P. & Losick, R. A family of membrane-embedded metalloproteases involved in regulated proteolysis of membrane-associated transcription factors. Proc. Natl Acad. Sci. USA 96, 14765–14770 (1999).

    CAS  PubMed  Google Scholar 

  136. 136

    Hoppe, T., Rape, M. & Jentsch, S. Membrane-bound transcription factors: regulated release by RIP or RUP. Curr. Opin. Cell Biol. 13, 344–348 (2001).

    CAS  PubMed  Google Scholar 

  137. 137

    Brown, M. S., Ye, J., Rawson, R. B. & Goldstein, J. L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391–398 (2000). An excellent analysis of the fascinating process that involves the participation of proteases that hydrolyze their substrates in the hydrophobic environment of the lipid bilayers.

    CAS  PubMed  Google Scholar 

  138. 138

    Hopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).

    CAS  Google Scholar 

  139. 139

    McLysaght, A., Hokamp, K. & Wolfe, K. H. Extensive genomic duplication during early chordate evolution. Nature Genet. 31, 200–204 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Samonte, R. V. & Eichler, E. E. Segmental duplications and the evolution of the primate genome. Nature Rev. Genet. 3, 65–72 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Ross, J., Jiang, H., Kanost, M. R. & Wang, Y. Serine proteases and their homologs in the Drosophila melanogaster genome: an initial analysis of sequence conservation and phylogenetic relationships. Gene 304, 117–131 (2003).

    CAS  PubMed  Google Scholar 

  142. 142

    Lespinet, O., Wolf, Y. I., Koonin, E. V. & Aravind, L. The role of lineage-specific gene family expansion in the evolution of eukaryotes. Genome Res. 12, 1048–1059 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Nardi, J. B., Martos, R., Walden, K. K., Lampe, D. J. & Robertson, H. M. Expression of lacunin, a large multidomain extracellular matrix protein, accompanies morphogenesis of epithelial monolayers in Manduca sexta. Insect Biochem. Mol. Biol. 29, 883–897 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Carlos López-Otín.

Supplementary information

Related links

Related links

DATABASES

LocusLink

ACE

ADAM33

ADAMTS13

APP

C1r

C1s

CAPN3

CAPN10

CASP10

CYLD

ELA1

Ela2

KLK3

LMAN1

MMP1

PSEN1

PSEN2

Ren2

Uchl4

Usp14

USP17

OMIM

Alzheimer disease

asthma

congenital neutropenia

cyclic haematopoiesis

familial cylindromatosis

haemophilia A

haemophilia B Leyden

Huntington disease

hyperhomocysteinemia

hyperprothrombinemia

limb-girdle muscular dystrophy type 2A

multiple myeloma

thrombotic thrombocytopenic purpura

type II autoimmune lymphoproliferative syndrome

type-2 diabetes

FURTHER INFORMATION

Celera Discovery System

Chris Overall's Laboratory

Ensembl

Interpro

Lopez-Otin's Laboratory

MEROPS

NCBI

Pfam

Protpars

SMART

Glossary

PROTEASOME

An intracellular protein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by ubiquitin.

NUCLEOPHILE

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.

ORTHOLOGUES

Homologous genes that have originated as a result of a speciation event.

PARALOGUES

Homologous genes that have originated as a result of a duplication event.

SYNTENY

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.

MEROPS

A database that provides a comprehensive catalogue and structure-based classification of proteases and inhibitors from a range of organisms.

EXOSITE

A substrate-binding site that lies outside the catalytic domain of a protease and is located on specialized substrate-binding modules or domains.

RETROTRANSPOSITION

The incorporation of DNA segments in a genome through a reverse-transcription-mediated mechanism.

AUTOPHAGY

A nutritionally and developmentally regulated process that is involved in the intracellular destruction of endogenous proteins and the removal of damaged organelles.

PARALOGONS

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.

GRANZYME

A serine protease that is produced by immune-system cells and stored in secretory granules.

COMPLEMENT

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.

PRODOMAIN

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.

CHAPERONE

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.

HAPLOINSUFFUCIENCY

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.

VASOPEPTIDASE

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.

PHARMACOKINETICS

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing