Biomedical Engineering Reference
In-Depth Information
average, selective pressure has been lost within the active site, and therefore this
region is likely to be of a markedly different importance to the function of the
inactive SMIPPs than for active trypsin-like serine proteases.
The phylogeny of the SMIPP family (Figure 10.3) is consistent with the early
duplication of a gene encoding an active enzyme, yielding the modern-day
SARS3-A1 enzyme and the common ancestor of all non-enzymatic members of
the family. Following this duplication, a significant lag period is observed,
followed by two duplications within a short period of time, and subsequently a
further series of expansions, yielding the modern-day repertoire of the parasite.
Maximum likelihood ancestral sequence reconstruction, based on codon data,
was used to infer sequences at ancestral nodes with the highest posterior
probability in PAML4.1. This analysis suggests that the common ancestor of
the inactive SMIPPs lost its enzyme activity prior to the expansion of the non-
enzymatic subfamily. Consistently, none of the SMIPPs appear to possess a
sequence that is intermediate between the enzymatically active and inactive
forms.
Other tests performed on the data indicated that there is significant hetero-
geneity in the rate of evolution between lineages (p
o
0.01), reflecting differences
in selective pressure operating on the different genes. Consequently, the data
are not clock-like, and it is not possible to infer actual dates for the divergence
events. Nevertheless, it was found that, over the course of their evolution, the
inactive SMIPPs have accumulated mutations in their amino acid sequence on
average 1.7-fold more rapidly than their enzymatic counterpart. Collectively,
these observations support the notion that the SMIPPs have acquired distinct
roles that have, in turn, altered the selective pressures to which they are subject.
10.6 SMIPPs Do Not Function by Competing for
Substrates with Host Proteases That Play a Role
in Host Defense Mechanisms
Although the proteolytically active member of the family, SARS3-A1, exhibits
the hallmarks of an active serine protease, the unique sequence and structural
features of the SMIPP family discussed above strongly suggest that this family
functions in a distinctly different way to a catalytically active serine protease.
Given the clear sequence homology with HDM serine protease allergens, and
the knowledge that scabies infestation elicits a delayed-type hypersensitivity
reaction, it is likely that SARS3-A1 and SMIPPs play a role in defense against
the host immunological response.
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Although it is plausible that the sequence
diversity within the SMIPP family represents an adaptation that enables scabies
mites to evade the host defense mechanisms, the structural data do not support
the hypothesis that this is in any way mediated by their capacity to bind peptide
substrates competitively, at least by a canonical protease-like mechanism. In
particular, the Tyr200 residue is anticipated to completely occlude the S1
subsite. In active serine proteases, proper interaction of the P1 residue of
substrates
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with the S1 site of the protease is a primary determinant of
