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.
(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.
(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.
AIDitional 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.