We have modeled the structure of human lymphotactin
(hLpnt), by homology modeling and molecular dynamics simulations.
This chemokine is unique in having a single disulfide bond
and a long C-terminal tail. Because other structural classes
of chemokines have two pairs of Cys residues, compared
to one in Lpnt, and because it has been shown that both
disulfide bonds are required for stability and function,
the question arises how the Lpnt maintains its structural
integrity. The initial structure of hLpnt was constructed
by homology modeling. The first 63 residues in the monomer
of hLpnt were modeled using the structure of the human
CC chemokine, RANTES, whose sequence appeared most similar.
The structure of the long C-terminal tail, missing in RANTES,
was taken from the human muscle fatty-acid binding protein.
In a Protein Data Bank search, this protein was found to
contain a sequence that was most homologous to the long
tail. Consequently, the modeled hLpnt C-terminal tail consisted
of both α-helical and β-motifs. The complete model
of the hLpnt monomer consisted of two α-helices located
above the five-stranded β-sheet. Molecular dynamics
simulations of the solvated initial model have indicated
that the stability of the predicted fold is related to
the geometry of Pro78. The five-stranded β-sheet appeared
to be preserved only when Pro78 was modeled in the cis
conformation. Simulations were also performed both for
the C-terminal truncated forms of the hLpnt that contained
one or two (CC chemokine-like) disulfide bonds, and for
the chicken Lpnt (cLpnt). Our MD simulations indicated
that the turn region (T30–G34) in hLpnt is important
for the interactions with the receptor, and that the long
C-terminal region stabilizes both the turn (T30–G34)
and the five-stranded β-sheet. The major conclusion
from our theoretical studies is that the lack of one disulfide
bond and the extension of the C-terminus in hLptn are mutually
complementary. It is very likely that removal of two Cys
residues sufficiently destabilizes the structure of a chemokine
molecule, particularly the core β-sheet, to abolish
its biological function. However, this situation is rectified
by the long C-terminal segment. The role of this long region
is most likely to stabilize the first β-turn region
and α-helix H1, explaining how this chemokine can function
with a single disulfide bond.
