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7. Sickle Hemoglobin

Sickle hemoglobin results from mutation of a single amino acid in the beta chain, with no change in the other 286 amino acids that make up the alpha and beta chains. Heterozygotes (having one good plus one mutant gene) are largely healthy. Homozygotes (having two mutant genes) suffer from severe sickle disease. There is an excellent 8-minute video about the cause, symptoms, and treatments for sickle disease (source). Carriers of the sickle mutation are resistant to malaria. As a consequence of this advantage, areas where malaria is endemic have a high frequency of sickle carriers.

When anoxic, sickle hemoglobin polymerizes into long protein fibers. These fibers distort red blood cells into a sickle-shape. Sickled red blood cells tend to clog capillaries, and break easily. The average lifetime of a normal red blood cell is about 120 days, which is reduced to less than 20 days in sickle disease. This leads to anemia and many other complications (see video link above).


Image sources: 1, 2.

The sickle mutation and the mechanism of fiber formation by sickle hemoglobin are illustrated below.

  Alpha, Beta, Deoxy-Heme. The mutation in sickle hemoglobin changes a single negatively-charged hydrophilic glutamic acid on the Beta chain surface (sequence position 6) to valine (hydrophobic, white).
  When deoxygenated, a small hydrophobic patch is exposed on the surface of the Alpha chain in both normal and sickle hemoglobin. This hydrophobic patch is part of the hydrophobic pocket holding the Heme.
  The mutant hydrophobic valine 6 sticks to the deoxy hydrophobic patch (excluding water) causing deoxygenated sickle hemoglobin to polymerize, forming long protein fibers that distort the red blood cell into a sickle shape.

Image source.
  Alpha, Beta, Deoxy-Heme, Mutant Valine 6, Hydrophobic Pocket. The beta-chain mutant valine-6 binds in a hydrophobic pocket that is exposed on the surface of the deoxy-conformation of the beta chain. Leucine 88 and Phenylalanine 85 have been confirmed as crucial for polymerization of sickle hemoglobin by mutational analysis (Adachi 1994a, Adachi 1994b, Adachi 1995).
  Here, we show only 2 strands of 8 molecules each, with each amino acid simplified to a single alpha-carbon atom. In reality, each sickle hemoglobin fiber has >1,000 molecules, and many fibers can form in a single cell. Each fiber consists of 7 pairs of strands (14 strands). One "strand" consists of a chain of >100 molecules -- an extension of the eight-molecule strand shown here.

Eight-minute video about the cause, symptoms, and treatments for sickle disease (source).

Excellent short review about the polymerization biochemistry of Hemoglobin S by Jessica Mackey.

References.

         

What Do You See?
  1. The beta chain of hemoglobin contains 146 amino acids. How many amino acids are changed in sickle hemoglobin?
  2. What does the mutation do to the chemical properties of the protein?
  3. Most people who have sickle hemoglobin have little or no sickle cell disease. Why?
  4. Sickle carriers with little or no disease have an advantage in some parts of the world. What is it?
  5. When the mutant sickle hemoglobin is the only form present, what happens to it in deoxygenated red blood cells? How does that cause disease?

Get immediate feedback at the practice quiz.

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