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topology, they may be much shorter or bent, as compared to the secondary
structure elements in sperm whale Mb. The most striking differences
between the 2-on-2 and the 3-on-3 globin folds are (i) the drastically short-
ened A-helix (completely deleted in group III 2/2HbP), (ii) the absence of
the D-helix, (iii) the presence of a long polypeptide segment (pre-F) in
extended conformation, and (iv) a variable-length F-helix (reduced to a
one-turn-helix in group I and III 2/2Hbs) that properly supports the
haem-coordinated proximal HisF8 residue (
Pesce et al., 2000; Milani
et al., 2003; Nardini et al., 2006
)(
Fig. 2.1
). Structural differences are evident
also on the haem distal side, where the 2/2 fold CD-D region differs in
length relative to (non-)vertebrate globins.
Structural superposition of 2/2Hbs of known structure highlights a gen-
eral good conservation of the
a
-helical scaffold among the three groups,
with the overall fold of group III 2/2HbP equally diverging in its
C
a
trace
from group I and group II 2/2Hbs. Interesting group-specific structural var-
iability/plasticity can be recognized at defined sites of the tertiary structure
and correlated to attainment and stabilization of the compact 2/2Hb fold. At
the N- and C-termini, the A-helix can be either very short or fully absent (as
in group III), while the H-helix is highly variable in length and linearity,
being kinked in group I, short in group II, unusually long in group III. Other
important structural variations are localized in the core of the protein. For
instance, the polypeptide stretch bridging the C- and E-helices is usually
trimmed to about three residues in group I 2/2HbNs and group II
2/2HbOs; on the contrary, a 3-7 amino acid insertion is invariantly found
in group III 2/2HbPs. Such elongation of the CD region has structural
implications on the spanning of the C- and E-helices and on the 3
10
helical
character of helix C. Indeed, in group III 2/2HbP from
C. jejuni
, the
C- and E-helices are elongated by one additional turn at their C- and
N-termini, respectively, relative to the corresponding helices in group
I and group II 2/2Hbs, not affecting, however, the position of the
E-helix relative to the haem distal site (
Nardini et al., 2006
). Variable
capping interactions in the CE inter-helical region of group III 2/2HbP,
however, suggest that secondary structure boundaries may not be conserved
and that C- and E-helix lengths, side chain locations, and haem accessibility
may differ across the group (
Nothnagel, Winer, et al., 2011
). Additionally, in
group III 2/2HbP, the C-helix displays a clear
a
-helical character, whereas it
is a 3
10
helix in group I and group II 2/2Hbs and in (non-)vertebrate
globins (
Bolognesi, Bordo, Rizzi, Tarricone, & Ascenzi, 1997
). Despite
the group-specific structural variations, in all 2/2Hbs, the CD region and
