Biomedical Engineering Reference
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through a region on loop1 of the serine protease-like domain of haptoglobin. In
serine proteases, loop1 determines S1 specificity, a factor which dictates the
substrate selectivity of the protease. 103
The combination of hemoglobin removal and a role in triggering the release
of anti-inflammatory cytokines makes haptoglobin an important anti-oxidant
and anti-inflammatory protein with a pivotal role in maintaining host
hemostasis. Inactive Proteases as Regulators
A serine protease homolog identified in the crab species Scyalla paramamosain
is able to bind to the bacterial crab pathogen Vibrio parahaemolyticus. 104 The
protease is homologous to the catalytically inactive prophenoloxidase activating
factor (PPAF) found in three other crab species. PPAFs are initiators of the
prophenoloxidase activating system or melaninization cascade, an important
immune mechanism in invertebrates. 105 As essential cofactors for propheno-
loxidase activating enzyme, they constitute one of four recognized regulatory
mechanisms. 106 Proteolytically active PPAFs comprise an N-terminal clip
domain and a carboxy-terminal serine protease domain. Clip domains have
been shown to regulate protease activity, engage in protein-protein interactions,
and perform bactericidal functions. In addition, the serine protease domain
cleaves prophenoloxidase. 105,107 Inactive PPAFs differ in having the serine
protease domain modified with non-synonymous substitutions of the catalytic
residues. In Scyalla paramamosain, a substitution of the catalytic residue serine
to glycine renders this serine protease catalytically inactive. 104 The inactive
protease was found to be tissue-specific, localized in the eye stalk, subcuticular
epidermis, stomach, gills, hemocytes, thorax ganglion, brain, and muscle.
Functional studies showed that after challenge with bacteria, its expression was
upregulated in the hemocytes, subcuticular epidermis, and gills. These organs
are considered frontline defense tissues, suggesting a role for the inactive PPAF
as an immune recognition molecule in crab antibacterial defenses. 104 Inactive Proteases Involved in Immune Function
A recent case study by Shah et al. systematically assigned functions to serine
proteases of Drosophila melanogaster using an extensive array of analytical and
bioinformatics tools. 108 The authors allocated functions to 35 of the 57 cata-
lytically inactive serine protease homologs identified by previous studies. 109 Of
the 35, 27 were assigned roles in immune responses. A study using RNAi
screening of serine proteases involved in Drosophila immune responses com-
plemented the findings of Shah et al., confirming the role of two of the serine
proteases in immune function. 110 Multifunctional Inactive Proteases
In humans, one of the best-described inactive serine proteases is human
heparin-binding protein (HBP) also known as Azurocidin or Cationic
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