Transcript Sickle Cell Anemia

Sickle Cell Anemia
Sickle Cell anemia is an inherited red blood cell
disorder. Normal red blood cells are round like
doughnuts, and they move through small blood tubes
in the body to deliver oxygen.
Sickle red blood cells become hard, sticky and shaped
like sickles used to cut wheat. When these hard and
pointed red cells go through the small blood tube, they
clog the flow and break apart. This can cause pain,
damage and a low blood count, or anemia.
The origin of the disease is a small
change in the protein hemoglobin
The change in cell structure arises from a change in
the structure of hemoglobin.
A single change in an amino acid causes hemoglobin
to aggregate.
The function of hemoglobin is
to carry oxygen
Hemoglobin A
Normal hemoglobin has
four subunits that each
contain an oxygen binding
site.
Biswal, B. K., Vijayan, M.:
Structures of Human Oxyand Deoxyhaemoglobin at
Different Levels of Humidity:
Variability in the T State
Acta Crystallogr., Sect.D
58 pp. 1155 (2002)
The origin of sickle cell anemia
is a mutation in hemoglobin
Hemoglobin S
A single mutation in
hemoglobin results in a
binding of one protein
to another.
Padlan, E. A., Love, W. E.:
Refined crystal structure of
deoxyhemoglobin S. I.
Restrained least-squares
refinement at 3.0-Å
resolution. J Biol Chem 260
pp. 8272 (1985)
Hemoglobin is a carrier protein
O2
HbO2
CO2
deoxy Hb (CO2)
Lungs
Tissues
Hemoglobin changes structure for
efficient oxygen uptake and delivery
HbO2
deoxy Hb (CO2)
Strong binding state
R state
Weak binding state
T state
Models for cooperativity
The cooperative R - T switch relies
on iron displacement to communicate
between a and b subunits
Hemoglobin is composed of two a and two b
subunits whose structures resemble myoglobin.
Eaton et al. Nature Struct. Biol. 1999, 6, 351
The small change in hemoglobin
structure leads to aggregation
a
b
Subunits
Normal hemoglobin (Hb A)
Sickle cell hemoglobin (Hb S)