Biomedical Engineering Reference
In-Depth Information
damage by either the classical or alternative pathways. The tick species Ixodes
scapularis and Ixodes ricinus produce a family of homologous salivary proteins,
termed the Isac-like protein family, that inhibit the alternative pathway.
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The parent protein Ixodes scapularis salivary anticomplement (Isac) was first
characterized as an inhibitor of the alternative pathway with the ability to
prevent the deposition of C3b and the release of C3a.
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Further characterization
by Valenzuela et al. confirmed that Isac prevented C3b and Factor B deposition
to an activated surface and was able to displace prebound Factor B. Valenzuela
et al. surmised that Isac acted as negative regulator, dissociating C3 convertase
(C3bBb), like the complement regulators Factor H or DAF. Eight years later,
the work of Tyson et al. on the Ixodes scapularis salivary protein 20 (Salp20)
explained the inhibitory mechanism.
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Salp20, which displays 83% homology to
Isac and is also a member of the Isac-like family, was shown to bind to the
alternative pathway positive regulatory protein properdin (P). The role of
properdin is to stabilise the C3 convertase (C3bBb) on activating surfaces, such
as pathogen membranes, and to inhibit cleavage of C3b by complement reg-
ulatory proteins. Properdin's ability to form stable intermediate complexes with
C3b (C3bP) and factor B (C3bBP) accelerates the association of C3b with factor
B and the formation of C3 convertase (C3bBb). In the absence of properdin,
C3b and C3bBb are subject to regulatory processes designed to control com-
plement activation and protect host tissue for complement-mediated attack.
C3b can be cleaved by factor I, while C3bBb undergoes spontaneous dis-
sociation or dissociation directed by the regulatory proteins DAF, complement
receptor 1, C4-binding protein, and factor H.
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Salp20 was shown to bind
directly to properdin, displacing it from C3 convertase and when complexed to
C3b. The direct interaction of Salp20 with properdin resulted in the destabili-
zation and decay of preformed C3 convertase (C3bBb) and prevented formation
of new C3 convertase from intermediate complexes.
88
The above examples demonstrate the variety of strategies used by parasites to
circumvent a highly complex and lethal immune defense system. The impor-
tance in understanding the mechanism of complement evasion in parasite
survival is demonstrated by the body of research aimed at targeting these
mechanisms for novel therapeutics.
4.5 Inactive Proteases in Other Organisms
Inactive proteases have been identified in many protease classes. They are
catalytically inactive due to substitutions of catalytic residues or structural
rearrangements obscuring the active site or the substrate-binding pocket. These
changes have resulted in many proteases acquiring new functions.
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Some have
become regulators of other proteases, while others have evolved to engage in
protein-protein interactions.
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Pils and Schultz carried out an extensive study
of 47 enzymatic domains across seven metazoan genomes. They identified
inactive homologs in all species they investigated and concluded that the evo-
lution of inactive enzymes was a commonly occurring event, in agreement with
an earlier study by Todd et al.
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The majority of the inactivated domains were
