Biomedical Engineering Reference
In-Depth Information
The wide prevalence and decreasing treatment ecacy for scabies indicate that
development of novel control strategies, in the form of vaccination or immu-
notherapy, is warranted; this is feasible as clinical immunity to scabies develops
in humans.
7,8
A comprehensive review of these aspects has recently been
published.
9
10.1.1 Scabies Mite Inactivated Protease Paralogues (SMIPPs)
The scarcity of molecular data on scabies is due to the diculty in obtaining
mites in sucient numbers, because the parasite burden is generally very low,
and no in vitro culture system for propagating mites is available. In order to
address this problem, using scabies mites from skin shed into the bedding of
severe crusted scabies patients, a sequence database has been created, allowing
the identification of gene homologs to major allergens of house dust mites
(HDM).
9-11
In particular, 33 genes homologous to the serine protease group 3
major allergen were identified. Remarkably, with one exception, all proteins
contain mutations in the catalytic triad. This suggests strongly that members
of this family cannot act as proteases by a known mechanism, and they
have accordingly been named Scabies Mite Inactivated Protease Paralogues
(SMIPPs).
12
10.2 Crystal Structural Analysis of SMIPPs
In order to begin to understand the structural basis for SMIPP function (or
lack of), the crystal structures of two representative SMIPPs (SMIPP-S-I1 and
SMIPP-S-D1) have been solved at 0.185 and 0.20 nm resolution respectively.
Both structures adopt the characteristic serine protease fold, albeit with large
structural variations over much of the molecule, with considerable structural
rearrangements within and around the active site. Structural analysis, discussed
in detail below, provides an explanation for the absence of protease function,
and suggests that, in contrast to active serine proteases, these molecules are
unable to bind substrates in a canonical fashion.
13
10.2.1 SMIPPs Adopt the Chymotrypsin-Like Serine
Protease Fold
Both structures adopt the chymotrypsin-like serine protease fold, with residues
12-229 and 1-235 visible in the electron density for SMIPP-S-I1 and SMIPP-S-
D1, respectively. Figure 10.1A and B shows a comparison of the structures
of each of the SMIPPs with human trypsin (PDB identifier 5PTP). Root Mean
Square Deviation (RMSD) (% sequence identities) between SMIPP-S-I1 and
SMIPP-S-D1, SMIPP-S-I1 and trypsin, and SMIPP-S-D1 and trypsin are 0.24
nm (40%), 0.29 nm (24%), and 0.18 nm (25%), respectively. The net RMSD
between all three structures is 0.24 nm.
