Comparing the molecular
structure differences between HbF and HbA that affect BPG binding
Fetal hemoglobin (HbF) is the predominant form of
hemoglobin expressed in the developing fetus. HbF appears in fetal blood a few weeks post-conception and
usually persists at some level in the new born for a few months post-birth. HbF is an
α2γ2
tetramer and while having exactly the same α-chains
as adult
hemoglobin (HbA), HbF has, by contrast, two gamma (γ)
polypeptide subunits that are highly homologous to the HbA
β-chains
but with significant structural differences as outlined in the table below.
These differences specifically alter BPG binding to HbF as compared to
HbA.
| HbF
γ-chain (charge) |
HbA
β-chain (charge) |
Qratio
= ΣQHbFγ/ΣQHbAβ
= relative average charge ratio
in or near fetal HbF BPG pocket |
Acetylated α-NH2-
Gly1-γ
(0) x2 |
α-NH3+-Val1-β
(+1) x2 |
Qratio
= 0 /+2 |
| Phe3-γ
(0) x2 |
Leu3-β
(0) x2 |
Qratio =
0 / 0 = 0
Phe3-γ pushes His2-γ
into BPG pocket
thereby altering imidazole ring interactions with
BPG |
| Asp80-γ
(-1) x2 |
Asn80-β
(0) x2 |
Qratio = -2
/ 0 |
| Ser143-γ
(0) x2 |
His143-β
(+1) |
Qratio = 0 /
+2 |
| Arg144-γ
(+1) x2 |
Lys144-β
(+1) |
Qratio = +2
/ +2 |
| ΣQHbFγ = 0 |
ΣQHbFg = +6 |
|
|
|
Net average charge difference on HbFγ2
compared
to HbAβ2
in or near the BPG pocket |
Qratio = ΣQHbFγ / ΣQHbAβ
= 0 / +6 |
- The primary structural differences
between HbF and HbA are located in or near the 2,3-BPG binding site between the
γ1-γ2
interface of HbF and the β1-β2
interface of HbA. The net effect of these
structural differences is that 2,3-BPG binds less tightly to deoxyHbF by comparison to deoxyHbA. Thus,
2,3-BPG does not stabilize the deoxyHbF as effectively as it stabilizes deoxyHbA, thus
accounting for the leftward shift of the O2 saturation curve of HbF compared to
HbA when tested with the same concentration of 2,3-BPG.
- As a consequence of the structural differences
between these two isoforms of hemoglobin, HbF exhibits a higher average affinity for
oxygen than HbA. This is demonstrated by the fact that the O2 saturation curve
for HbF is shifted to the left relative to the saturation curve for HbA when tested under identical
experimental conditions. This shift is physiologically meaningful because some
of the O2
in maternal blood must diffuse to the fetal circulation since this is the only
source of oxygen for the fetus. With higher average of affinity than HbA, HbF insures that
some of the maternal O2 will be trapped by the fetal circulatory
system.
- Thus, BPG binding affinity at the γ-interface of
deoxyHbF is destablized by both:
- The decrease in four positive charges (i.e.,
resulting from the neutral acetylated N-terminal Gly1-γ and
Ser143-γ residues) that are
available in HbA for forming salt bridges with BPG negative charges; and
- The presence of two additional negative charges
(i.e., associated with Asp80-γ) that tend to
repel the negative charges of BPG.
