Sickle Cell Anemia

1
Sickle Cell Anemia

• Sickle Cell anemia is an inherited red blood cell
  disorder. Normal red blood cells are round like
  doughnuts, and they move through small blood
  tubes in the body to deliver oxygen.
• Sickle red blood cells become hard, sticky and
  shaped like sickles used to cut wheat. When these
  hard and pointed red cells go through the small
  blood tube, they clog the flow and break apart.
  This can cause pain, damage and a low blood
  count, or anemia.

2
The origin of the disease is a small change in
the protein hemoglobin

• The change in cell structure arises from a change
  in
• the structure of hemoglobin.
• A single change in an amino acid causes
  hemoglobin
• to aggregate.

3
The function of hemoglobin is to carry oxygen
Hemoglobin A Normal hemoglobin has four subunits
that each contain an oxygen binding site.
Biswal, B. K., Vijayan, M. Structures of Human
Oxy- and Deoxyhaemoglobin at Different Levels of
Humidity Variability in the T State Acta
Crystallogr., Sect.D 58 pp. 1155 (2002)
4
The origin of sickle cell anemia is a mutation in
hemoglobin
Hemoglobin S A single mutation in hemoglobin
results in a binding of one protein to another.
Padlan, E. A., Love, W. E. Refined crystal
structure of deoxyhemoglobin S. I. Restrained
least-squares refinement at 3.0-Å resolution. J
Biol Chem 260 pp. 8272 (1985)
5
Hemoglobin is a carrier protein
O2
HbO2
CO2
deoxy Hb (CO2)
Tissues
Lungs
6
Hemoglobin changes structure for efficient oxygen
uptake and delivery
HbO2
deoxy Hb (CO2)
Strong binding state R state
Weak binding state T state
7
Models for cooperativity
8
The cooperative R - T switch relies on iron
displacement to communicate between a and b
subunits
Hemoglobin is composed of two a and two b
subunits whose structures resemble myoglobin.
Eaton et al. Nature Struct. Biol. 1999, 6, 351
9
The small change in hemoglobin structure leads to
aggregation
a b
Subunits
Normal hemoglobin (Hb A)
Sickle cell hemoglobin (Hb S)