Under anaerobic conditions, sickle cell
hemoglobin - Hb S - polymerizes into highly elongated cables. In the red blood cell (RBC)
such polymers distort its shape and suppleness resulting in a sickle-like
appearance as compared to the donut shape of a normal RBC. The rigid and
distorted sickled RBC has difficulty passing through the small capillary thereby
blocking
blood flow. However, only deoxy-Hb S, and not oxy-Hb S,
polymerizes as is consistent with the fact that RBC sickling occurs in the capillaries
where the O2 concentrations are relatively low and the deoxy-Hb S concentration
is relatively high. The sickle cell phenotype arises from a single mutation in the
b-globin gene
resulting in an amino acid substitution at the sixth residue of the b-chain with
b-Val6 in
Hb S
substituted for b-Glu6 in normal HbA. The hydrophobic
b-Val6 sidechains are exposed on the surface of the two
b-chains of
Hb S and
they can fit into hydrophobic pockets created by the sidechains of b-Phe85 and
b-Leu88 also on the
b-chain surface. The
spacing between these residues is such that deoxy-Hb S molecules self-associate and
polymerize. However, the geometrical spacing between these residues is different
for the oxy-Hb S conformer and it does not polymerize. The proposed interactions between
deoxy-Hb S molecules are illustrated by the structure of the Hb S
dimer.