Proteases and Human Disorders


Cells use proteases to cleave proteins to accomplish a variety of specific functions, particularly activation or inactivation of the target protein. Mutations resulting in altered proteolysis are implicated in a growing list of human diseases.

Keywords: angelman syndrome; hemophilia; epilepsy; protease; proteasome; proteolysis; thrombophilia; ubiquitin

Figure 1.

Diagram of the ubiquitin–proteasome pathway of proteolysis. In an adenosine 5′ triphosphate (ATP) dependent reaction, ubiquitin (Ub) forms a thiol ester with the E1 ubiquitin‐activating enzyme. It is then transferred to an E2 ubiquitin‐conjugating enzyme, and then typically to an E3 ubiquitin protein ligase. This enzyme transfers ubiquitin to multiple lysine residues on the target protein and links ubiquitin in polymeric chains. The multi‐ and polyubiquitinylated target protein enters the center of the proteasome, a multisubunit protease complex, where it is hydrolyzed to oligopeptides and regenerated ubiquitin monomers in an ATP‐dependent reaction.

Figure 2.

Activation and inactivation of the serine protease factor V. Factor V circulates in the blood as an inactive proenzyme. Upon its cleavage by the serine protease thrombin, it becomes the active serine protease factor Va. This form is in turn inactivated by proteolytic cleavage by the serine protease activated protein C (APC) and its cofactor protein S. The mutation in factor V Leiden allows its activation but slows its inactivation, resulting in an accumulation of factor Va, which promotes a tendency toward excessive blood clotting.



Chan CTJ, Clayton‐Smith J, Cheng XJ, et al. (1993) Molecular mechanisms in Angelman syndrome: a survey of 93 patients. Journal of Medical Genetics 30: 895–902.

Ciechanover A, Orian A and Schwartz AL (2000) Ubiquitin‐mediated proteolysis: biological regulation via destruction. BioEssays 22: 442–451.

Dahlback B (1999) Activated protein C resistance and thrombosis: molecular mechanisms of hypercoagulable state due to FVR506Q mutation. Seminars in Thrombosis and Hemostasis 25: 273–289.

Eriksson S (1989) Alpha‐1‐antitrypsin deficiency: lessons learned from the bedside to the gene and back again. Chest 95: 181–189.

Kato GJ (1999) Human genetic diseases of proteolysis. Human Mutation 13: 87–98.

Mannucci PM and Tuddenham EG (2001) The hemophilias – from royal genes to gene therapy. New England Journal of Medicine 344: 1773–1779.

Pennacchio LA, Lehesjoki A‐E, Stone NE, et al. (1996) Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271: 1731–1734.

Poort SR, Rosendaal FR, Reitsma PH and Bertina RM (1996) A common genetic variation in the 3‐prime‐untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88: 3698–3703.

Richard I, Broux O, Allamand V, et al. (1995) Mutations in the proteolytic enzyme calpain 3 cause limb‐girdle muscular dystrophy type 2A. Cell 81: 27–40.

Seligsohn U and Lubetsky A (2001) Genetic susceptibility to venous thrombosis. New England Journal of Medicine 344: 1222–1231.

Vu PK and Sakamoto KM (2000) Ubiquitin‐mediated proteolysis and human disease. Molecular Genetics and Metabolism 71: 261–266.

Further Reading

Ciechanover A, Orian A and Schwartz AL (2000) Ubiquitin‐mediated proteolysis: biological regulation via destruction. BioEssays 22: 442–451.

Furie B and Furie BC (1992) Molecular and cellular biology of blood coagulation. New England Journal of Medicine 326: 800–806.

Huang Y and Wang KK (2001) The calpain family and human disease. Trends in Molecular Medicine 7: 355–362.

Jagoe RT and Goldberg AL (2001) What do we really know about the ubiquitin–proteasome pathway in muscle atrophy? Current Opinion in Clinical Nutrition and Metabolic Care 4: 183–190.

Lijnen HR (2001) Elements of the fibrinolytic system. Annals of the New York Academy of Sciences 936: 226–236.

McCawley LJ and Matrisian LM (2001) Matrix metalloproteinases: they're not just for matrix anymore! Current Opinion in Cell Biology 13: 534–540.

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

Web Links Ubiquitin protein ligase E3A (human papilloma virus E6‐associated protein, Angelman syndrome) (UBE3A); Locus ID: 7337. LocusLink:‐post/Omim/dispmim?601623

Ubiquitin protein ligase E3A (human papilloma virus E6‐associated protein, Angelman syndrome) (UBE3A); MIM number: 601623. OMIM:

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Kato, Gregory J(Sep 2005) Proteases and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005165]