Biomedical Engineering Reference
In-Depth Information
The association of peptides into
trimeric
coiled coil seems in general
to be determined by hydrophobic residues in positions
a
and
d
of the
heptad repeat, apart from specific effects such as hydrogen-bonding
effects [38]. The
a
and
d
residues in the core pack as 'knobs-into-holes'
[39], where the 'hole' is in between two residues. Glu, Arg and Lys are
often found in
e
and
g
positions. Also, hydrophobic interactions
between side chains of
b
and
e
are more important for stabilizing a
trimer than a dimeric assembly. While two-stranded structures only
have substantially apolar residues at positions
a
and
d
(with the
remaining being highly polar), three-stranded coils show decreasing
polarity in other residues in moving away from the central axis (and
toward the solvent-exposed surface). Although the substitution of a
hydrophobic residue in position
a
or
d
by a hydrophilic residue is likely
to destabilize the protein, the resulting buried polar interaction may
favour one aggregational state over another (i.e. by negative design)
and thus contribute to a more native-like behaviour.
In coiled coils with three parallel strands, all the
a
residues form one
layer, while the
d
residues form another; the two types of layers are not
geometrically equivalent. In the antiparallel structure there are alternat-
ing layers of either two
a
and one
d
or one
a
and two
d
. While the parallel
orientation provides three identical helix-helix interfaces with interac-
tions between residues
e
and
g
, the antiparallel structures have
geometrically distinct interfaces, providing
g
-
g
,
g
-
e
and
e
-
e
interactions
(Figure 6.5).
Interestingly, the coil-Ser protein from DeGrado and coworkers,
which has an all-Leu core with Leu in positions
a
and
d
,formsan
antiparallel trimer [64,65]. The extensively studied 'coil-Ser' sequence
byDeGradoandcoworkersincorporatedTrp-2andHis-28tofacil-
itate NMR and UV spectroscopy. It had Leu in positions
a
and
d
(except Trp-2) and Glu and Lys at positions
e
and
g
.Itformedatrimer
both in solution, as observed by ultracentrifugation, and in the crystal,
as studied by X-ray crystallography. All helices had eight helical turns
and the trimer formed a hydrophobic core with eight hydrophobic
layers. The crystal structure revealed an antiparallel triple-stranded
a-helical bundle 44
˚
in length and 18
˚
in diameter. Helix I and II
were 'up' while helix III was 'down' (up-up-down topology; like an
'N'). The crossing angle between all three helix pairs was about
þ
20
and the three helices wrapped around the superhelical axis to form one
sixth of a turn of a left-handed super coil. The distance between the
axes of the helices was in the range 11.1-12.6
˚
. In solution, it
exhibited a monomer-dimer-trimer equilibrium.
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