The mutated form of hemoglobin (hemoglobin S, or HbS) in sickle-cell anemiaresults from the replacement of a glutamate residue by a valine residue at position 6 in the chain of the protein. (Normal hemoglobin is HbA.)

 

HbS has normal shape under normal conditions, but under conditions of low [O2] the hemoglobin forms fibrous aggregations, giving the entire red blood cell a sickle shape. Sickled red blood cells are relatively inflexible and may clog capillary beds, causing pain and tissue damage. The red blood cells also have a shorter life span, leading to anemia.

(a) Which of the following amino acids would you expect to produce a similar sickling effect if placed at position 6? Select all that apply.

1. Arginine

2. Leucine

3. Lysine

4. Alanine

5. Phenylalanine

(b) Sickling occurs in deoxyhemoglobin, but not in oxyhemoglobin. Normal deoxyhemoglobin (HbA and HbS) molecules have a small hydrophobic “pocket” on the surface of a ? chain. In oxyhemoglobin, however, this pocket is located toward the interior of the hemoglobin molecule. From what you know about the sickle-cell mutation and disease, determine which two amino acids make up this pocket.

1. Valine

2. Glutamate

3. Glutamine

4. Phenylalanine

5. Lysine

(c) How does aggregation occur in sickle-cell anemia? Place the steps in the correct order from no aggregation to sickle red blood cell. Note that deoxyhemoglobin is generally in the T state; oxyhemoglobin is in the R state.

Additional T state HbS interact with the growing aggregation to form an insoluble fiber.

Val interacts with the “pocket” of a beta chain on another HbS.

R state Hb shifts to T state Hb

O2 decreases due to vigorous exercise or high altitude.