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9. Replacement of an A by a T in a region of the human gene for the B chain of hemoglobin is associated with sickle-cell anemia:

Normal: 5′-ATGGTGCACCTGACTCCTGAGGAGAAGTCT-3′

Sickle cell: 5′-ATGGTGCACCTGACTCCTGTGGAGAAGTCT-3′

(a) What is the nucleotide sequence of the normal and sickle-cell hemoglobin mRNA?

(b) What is the amino acid sequence in this part of the Bpolypeptide chain, and what is the amino acid replacement that results in sickle-cell hemoglobin?

(c) Why might this amino acid substitution make a difference in protein structure?

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Related questions

Normal adult hemoglobin is called Hemoglobin A (Hb A). Ninety-eight percent of adult hemoglobin is Hb A and 2% is Hb A2. There are other forms of hemoglobin. For example, the developing fetus has a different kind of hemoglobin than most normal adults. Fetal hemoglobin (Hb F) is synthesized beginning at the third month of gestation and continues up through birth. After the neonate is born, hemoglobin F synthesis declines (because synthesis of the (chain declines) and hemoglobin A is synthesized. By the time the baby is six months old, 98% of its hemoglobin is Hemoglobin A. There is also a mutant form of hemoglobin called Hemoglobin S, which is found in persons with the disease sickle cell anemia. The disease sickle cell anemia is one of the major health problems facing the African-American community. The World Health Organization estimates that 250,000 babies world wide are born with sickle cell anemia. Currently there is no cure. A person afflicted with sickle cell anemia has inherited a defective gene from each parent. The defective gene is the one coding for the β-chain. The amino acid at position 6 on each β chain has been mutated from a glutamate to a valine. Normal α chains have a decreased affinity for the mutated β chains; thus assembly of the HbS tetramer is more difficult. Red blood cells containing HbS form a sickle shape because the Hb S molecules polymerize. Hb S molecules are more likely to polymerize when in the deoxygenated T form than in the oxygenated R form. The polymerized Hb deforms the normal discoid shape of the red blood cells, producing a sickle-shaped cell. The sickle shaped red blood cells become trapped in capillaries and organs, depriving the victim of adequate oxygen supply and causing chronic pain and organ damage.

Glover, R. E., Ivy, E. D., Orringer, E. P., Maeda, H., and Mason, R. (1999) Molecular Pharmacology 55, pp. 1006-1010.

Huang, J., Hadimani, S. B., Rupon, J. W., Ballas, S. K., Kim-Shapiro, D. B., and S. Bruce King (2002) Biochemistry 41, pp. 2466-2474.

S. Bruce King (2003) J.Clin. Invest., 111, pp. 171-172.

1) Why do you think Hb S has higher tendency to polymerize compared to Hb A?

16. Sickle cell anemia is a genetic disorder resulting in an alternation of the structure and function of hemoglobin. Specifically, the amino acid valine replaces glutamate in a position located in the surface of the protein. Based on your knowledge of protein sequence answer the following:

a. At what level of protein structure does the amino acid substitution occur? Explain?

b. Provide a biochemical rationale for why this change in the sequence of hemoglobin’s beta chain results in red blood cells sickling. Your answer should include reference to structures of valine and glutamine shown above.

Below is the protein sequence for the beta subunit of human hemoglobin (using the one letter abbreviations for amino acids). Use it to answer the following questions.

Write the order of the LAST 10 amino acids in this protein.

For each of the LAST 10 amino acids, tell one other amino acid that it would favorably interact with (i.e. could form a bond with).

In sickle cell anemia, the first glutamate (E) is mutated to valine (V). Propose a hypothesis on how this change of amino acid will affect the folding of the hemoglobin protein and why the hemoglobin function will change.

 MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH

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