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the E-, F-, and G-helices build the protein crevice hosting the haem, which
is shielded from the solvent and stabilized by well-conserved polar/electro-
static interactions involving the porphyrin propionates.
A stable and properly structured haem crevice in the context of such a
short polypeptide chain has been correlated to the presence of three glycine
motifs, conserved among sequences of group I 2/2HbNs and group II
2/2HbOs. Such Gly motifs are located at the AB and EF inter-helical
corners, and just before the short F-helix; they are thought to provide the
protein backbone flexibility needed to stabilize the short A-helix in a
conformation locked onto the B- and E-helices, and to support the pre-F
segment in building the haem pocket ( Milani et al., 2001; Pesce et al.,
2000 ). A similar stabilization, however, cannot be achieved in group III
2/2HbPs, where the AB Gly-Gly motif is absent, due to full deletion of
the A-helix. As a consequence, the 2/2HbP amino-terminus cannot face
the BE inter-helical region, and the protein residues preceding the
B-helix extend towards the GH region; such conformation is opposite to
that found in group I and II 2/2Hbs. Similarly, a clear Gly-Gly motif cannot
be recognized in the EF region of group III 2/2HbP, although scattered Gly
residues are present in this region of the sequence. Despite the absence of a
clear EF Gly-Gly motif, B- and E-helices in group III 2/2HbPs are oriented
as in groups I and II, their stabilization being achieved through group-
specific hydrophobic contacts at the B/E helical interface.
Other group-specific structural variation is localized inside the haem
binding pocket, with group III 2/2HbPs displaying a high degree of
similarity in sequence and structure of the distal region to group II 2/2HbOs
and, simultaneously, sharing a proximal side-extended EF region typically
found in group I 2/2HbNs. Structural differences and group-specific
residues at the haem distal and proximal sites are correlated to different
ligand-binding properties of 2/2Hbs.
3. THE HAEM ENVIRONMENT
Despite the trimmed globin fold, the 2/2 helical sandwich provides a
minimal scaffold, formed by the E- and G-helices, by the CD region and by
the F-helix, that allows efficient incorporation of the haem group within the
protein ( Fig. 2.1 ). Besides the HisF8-Fe coordination bond, in all 2/2Hbs,
the haem is stabilized by a network of van der Waals contacts with hydro-
phobic residues at the conserved topological positions C6, C7, CD1, E14,
F4, FG3, G8, and H11. Other protein-haem interactions may arise from
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