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What Causes Sickle Cell Anemia?
Sickle
Cell and Hemoglobin S
Sickle cell
anemia is an inherited condition. People with sickle cell anemia
inherit two copies of the sickle cell gene, one from each parent.
The
sickle cell gene makes abnormal hemoglobin called Hemoglobin-S.
In sickle
cell anemia, the abnormal hemoglobin (Hemoglobin-S) sticks together
when it gives up its oxygen to the tissues. These clumps cause
red blood cells to become stiff and shaped like a sickle.It takes
two copies of the sickle cell gene for the body to make the abnormal
hemoglobin found in sickle cell anemia
Sickle
Cell Trait
.People who
inherit only one copy of the sickle cell gene (from one parent)
will not have sickle cell anemia. They will have sickle cell trait.
People who
have sickle cell trait generally have no symptoms and lead normal
lives. Like people with sickle cell anemia, however, they can
pass the sickle cell gene on to their children.
How is
Hemoglobin Different in the Sickle Cell?
Hemoglobin
is the iron-containing oxygen-transport metalloprotein in the
red blood cells of the blood in vertebrates and other animals.
In mammals the protein makes up about 97% of the red cell’s dry
content, and around 35% of the total content (including water).
Hemoglobin transports oxygen from the lungs to the rest of the
body, such as to the muscles, where it releases the oxygen.
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To
view Hemoglobin S molecule using Chime 3D
PDB
FILE: 2HBS
Harrington,
D.J., Adachi, K., Royer Jr., W.E. (1997) The high resolution
crystal structure of deoxyhemoglobin S. J.Mol.Biol. 272:
398-407
The Hydrophobic Pocket
The
interaction between Val 6 (yellow) on one chain of one hemoglobin
molecule and a hydrophobic patch formed by Phe 85 (blue)
and Leu 88 (gey) on a chain of another deoxygenated hemoglobin
molecule leads to hemoglobin aggregation.
double click for backbone structure showing pocket
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Sickle-cell
anemia is caused by a point mutation in the ß-globin chain of
hemoglobin, replacing the amino acid glutamic acid with
the less polar amino acid valine at the sixth position of the
ß chain. The Glu 6 Val mutation in deoxy-HbS favors
a hydrophobic interaction between each strand and its neighbor.
The
abnormal hemoglobin in which valine has replaced glutamic acid
causes the hemoglobin to become less soluble under decreasing
oxygen concentrations and to polymerize into crystals that distort
the red blood cells into a sickle shape.
At the molecular
level the interaction between Val 6 on one chain of one hemoglobin
molecule and a hydrophobic patch formed by Phe 85 and Leu 88 on
a chain of another deoxygenated hemoglobin molecule leads to hemoglobin
aggregation. See
for image
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