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)