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for homology identification lacks the sensitivity to recognize the
homology between a significant fraction of pairs of family mem-
bers. Secondary structure prediction methods may reveal predomi-
nately helical structure but with little specificity for particular
topologies. Methods to predict amphipathic helical regions from
sequence (
45
) are useful but again lack the necessary specificity for
the helical cytokine fold, being easily attracted to long coiled-coil
structural regions. These difficulties motivated the creation of a
new approach specifically tailored to the helical cytokines (
40
)
which achieves high sensitivity at an acceptable level of specificity.
The basic operation of this method is to “thread” a sequence
through a core of amphipathic helical profiles, its specificity arising
from the cumulative contribution of each helix and the compliance
of the loop region lengths to permissible ranges. The method was
used to directly discover or support the inference of several human
helical cytokines from EST and genomic sequence (
40
); particu-
larly IL-19, IL-20, IL-21, IL-27, IL-29 (Fox et al. (
46
) describe in
more detail the computational identification of the interferon
lambda family), and IL-31. A list of the known human helical
cytokines is given in Table
4
.
3
4-Alpha-Helical Cytokines in Invertebrates
Studies on invertebrates gained high respectability in the field of
innate immunity as a lot has been learned in the
Drosophila
on key
molecules in this pathway, such as the Toll-like receptors and the
transcription factor NF-kB. Many cytokines have been described
in invertebrates (
47-50
). Though helical cytokines have been
reported in all vertebrate genomes, in invertebrate genomes
orthologous vertebrate cytokines have not been identified.
Nevertheless, intriguing evidence for their existence arises from
several sources, including: orthologous receptors, which presum-
ably would bind a ligand of the helical cytokine structure, struc-
tural prediction and data mining of transcriptomes, and
immunoreactivity to vertebrate cytokine antibodies. In
Drosophila
the DOME receptor belongs mediates phosphorylation of a JAK
orthologue through a ligand known as UPD
,
which has no homol-
ogy to a known helical cytokine and does not demonstrate the
features of a helical cytokine in its sequence (
51, 52
). Data mining
of Drosophila transcripts revealed a protein known as HF (helical
factor) that has an amphipathic helical structure and topology
consistent with the helical cytokine fold (
52
) though this can only
be conclusively known through structure determination. In the
invertebrate chordate
Ciona intestinalis
data mining of putative
coding exons revealed two cytokine receptors (
53
), though their
ligands have not been identified.
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