Families and clans of cysteine peptidases

The Babraham Institute Peptidase Laboratory, Department of Immunology CB2 4AT Cambridge UK
Perspectives in Drug Discovery and Design 01/1996; 6(1):1-11. DOI: 10.1007/BF02174042


The known cysteine peptidases have been classified into 35 sequence families. We argue that these have arisen from at least five separate evolutionary origins, each of which is represented by a set of one or more modern-day families, termed a clan. Clan CA is the largest, containing the papain family, C1, and others with the Cys/His catalytic dyad. Clan CB (His/Cys dyad) contains enzymes from RNA viruses that are distantly related to chymotrypsin. The peptidases of clan CC are also from RNA viruses, but have papain-like Cys/His catalytic sites. Clans CD and CE contain only one family each, those of interleukin-1-converting enzyme and adenovirus L3 proteinase, respectively. A few families cannot yet be assigned to clans. In view of the number of separate origins of enzymes of this type, one should be cautious in generalising about the catalytic mechanisms and other properties of cysteine peptidases as a whole. In contrast, it may be safer to generalise for enzymes within a single family or clan.

7 Reads
  • Source
    • "When the gels were incubated in the presence of PMSF , a mechanism - based inhibitor commonly used to identify serine - type proteinases ( Polga´r , 2004 ) , the cleared zones of substrate proteolysis were no longer visible . Inclusion of E - 64 , a mechanism - based inhibitor of cysteine proteinases ( Rawlings and Barrett , 2004 ) , did not affect the activities seen , indicating that hydrolysis of the incorpo rated beta - amylase substrate was mediated by serine - class proteinases , and not by cysteine - class proteinases . The high MW proteinase activity identified as spot 3 on the control gel did not focus well in the bottom gel , with a diffuse band of proteinase activity appearing to streak along the top of the second dimension gel . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteolytic degradation of barley proteins is examined in green (unkilned) malt and germinating seeds from Hordeum vulgare L. cv. Harrington. Zymographic analysis of the Harrington green malt extracts using commercial preparations of barley beta-amylase incorporated as a proteolytic substrate in 2-D SDS gels shows multiple proteolytic activities. A developmental study shows that the several green malt beta-amylase-degrading activities appear at around day 2 of germination. The several activities appear to increase and decrease through 7 days of germination in a coordinated fashion. Gels treated with class-specific proteinase inhibitors show that serine-class proteinase activities are responsible for barley beta-amylase degradation seen on the zymograms. Western blot analysis also shows that proteolytic enzymes recovered from 1-D electrophoretic gels degrade barley beta-amylase, and that the degradation is inhibited by PMSF. This is the first demonstration that malt proteinases are capable of degrading important metabolic enzymes in germinating barley, and the first postulated physiological role for the serine class proteinases in barley malt.
    Journal of Cereal Science 05/2008; 47(3-47):480-488. DOI:10.1016/j.jcs.2007.06.002 · 2.09 Impact Factor
  • Source
    • "The known cysteine proteinases have been classified into 35 sequence families numbered Cl, C2, etc. (Barrett and Rawlings, 1996). The authors argue that it is probable that some families have common ancestors which are so ancient that no significant similarities in amino acid sequence survive. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cysteine proteases of Porphyromonas gingivalis are extracellular products of an important etiological agent in periodontal diseases. Many of the in vitro actions of these enzymes are consistent with the observed deregulated inflammatory and immune features of the disease. They are significant targets of the immune responses of affected individuals and are viewed by some as potential molecular targets for therapeutic approaches to these diseases. Furthermore, they appear to represent a complex group of genes and protein products whose transcriptional and translational control and maturation pathways may have a broader relevance to virulence determinants of other persistent bacterial pathogens of human mucosal surfaces. As a result, the genetics, chemistry, and virulence-related properties of the cysteine proteases of P. gingivalis have been the focus of much research effort over the last ten years. In this review, we describe some of the progress in their molecular characterization and how their putative biological roles, in relation to the in vivo growth and survival strategies of P. gingivalis, may also contribute to the periodontal disease process.
    Critical Reviews in Oral Biology & Medicine 02/2001; 12(3):192-216. DOI:10.1177/10454411010120030101
  • Source
    • "Cysteine proteases of the papain superfamily, designated Clan A, family C1 (Barrett and Rawlings, 1996), are synthesised as zymogens that are activated by cleavage of the pro-domain to generate mature enzymes located predominantly within lysosomes. Trafficking of the mammalian proteases is mediated primarily through binding of mannose-6-phosphate residues present on the surface of the enzymes to appropriate receptors (Kornfeld and Mellman, 1989). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Removal of the pro-domain of a cysteine protease is essential for activation of the enzyme. We have engineered a cysteine protease (CPB2.8) of the protozoan parasite Leishmania mexicana by site-directed mutagenesis to remove the active site cysteine (to produce CPB(C25G)). When CPB(C25G) was expressed in a L. mexicana mutant lacking all CPB genes, the inactive pro-enzyme was processed to the mature protein and trafficked to the lysosome. These results show that auto-activation is not required for correct processing of CPB in vivo. When CPB(C25G) was expressed in a L. mexicana mutant lacking both CPA and CPB genes, the majority of the pro-enzyme remained unprocessed and accumulated in the flagellar pocket. These data reveal that CPA can directly or indirectly process CPB(C25G) and suggest that cysteine proteases are targeted to lysosomes via the flagellar pocket. Moreover, they show that another protease can process CPB in the absence of either CPA or CPB, albeit less efficiently. Abolition of the glycosylation site in the mature domain of CPB did not affect enzyme processing, targeting or in vitro activity towards gelatin. This indicates that glycosylation is not required for trafficking. Together these findings provide evidence that the major route of trafficking of Leishmania cysteine proteases to lysosomes is via the flagellar pocket and therefore differs significantly from cysteine protease trafficking in mammalian cells.
    Journal of Cell Science 12/2000; 113 ( Pt 22)(22):4035-41. · 5.43 Impact Factor
Show more