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Sickle Cell Anemia
Jenny Pham
Protein Structure & Function
Spring 2015
Outline
I.
Normal Adult Hemoglobin (Hb A)
a. Function: Deoxygenated v. Oxygenated
II. Mutation in Hb A
a. Sickle Cell Hemoglobin (Hb S)
III. Sickle Cell Anemia
a. Background
b. Medical/Biological Nature
c.
Biochemical Nature (Pathophysiology)
d. Treatment
Introduction
Hemoglobin (Hb A)
•
Function: Transport oxygen and other
gases throughout the body via
erythrocytes (red blood cells, or RBCs).
•
Quaternary Structure: 4 Chains
(Domains)
– 2 α + 2 β Chains

Each chain is comprised of 8 α
helices connected by 7 loop
regions.

•
No β strands.
Heme molecule bound within pocket
created by the α helices of each chain.
PDB: 1HHO
Method: X-Ray Diffraction
Resolution: 2.10 Å
Ligand: Heme Group
•
Heterocyclic Ring Structure: Protoporphyrin IX
– 4 Pyrroles Surrounding the Fe2+ Ion
•
Location of O2 binding
Hemoglobin Binding to Oxygen
Close Up of Oxygen Binding to the Heme Group in Hemoglobin
•
Deoxygenated Hemoglobin (Left: 2HHB)
•
Oxygenated Hemoglobin (Right: 1HHO)
Mutation: Hemoglobin S (Hb S)
•
Results from a point mutation of a thymine
to a adenine at the 17th nucleotide in the βglobin gene on chromosome 11.
– Causing for the 6th amino acid on the β-
chains to change from glutamic acid
(red) to valine (green).
Hb A vs. Hb S
Normal Adult Hemoglobin
PDB: 2HHB
Method: X-Ray Diffraction
Resolution: 1.74 Å
Hemoglobin S (Sickle)
PDB: 2HBS
Method: X-Ray Diffraction
Resolution: 2.05 Å
•
Point mutation responsible for the distortion of
normal RBCs into sickle-shaped RBCs.
– Normal RBCs: pliable, biconcave discs
– Sickled RBCs: stiff, sticky
•
Deoxygenated Hb S causes for hemoglobin polymers
to form, disrupting the cytoskeleton of the RBC that
forms protrusions (sickle shape).
– Interruption of the membrane attachment to the
cytoskeleton leads to the exposure of negatively
charged glycolipids, resulting in the blockage of
blood circulation.
Sickle Cell Anemia (SCA)
•
It’s an autosomal recessive
disorder that is characterized by
the homozygous inheritance of the
βs allele (HbSS).
– Must inherit sickle cell trait
from both parents.
•
Most common type of sickle cell
disease.
Prevalence for SCA
•
Most Common Genetic Disorder in
US – Affecting 70,000 – 100,000
Individuals
– Primarily African Americans =
1 in 500
•
Common in People from Africa,
South and Central America,
Caribbean Islands, Mediterranean
Islands, India, and Saudi Arabia
– Distribution of HbS allele
correlated to the distribution
of malaria – parasites that
thrive in normal RBCs cannot
survive in sickled RBCs.
Medical/Biological Nature of SCA
•
SCA is present at birth but does not manifest
until 4 months after birth.
•
Early diagnosis at birth can lengthen lifespan
with blood test.
– Using amniotic fluid or placenta tissue
can be used to diagnose SCA before birth.
•
Signs & Symptoms Vary – can range from
mild to severe
– Linked to Anemia and Pain
•
Numerous Complications
– Examples: Increased Risk of Infections,
Splenic Crisis, Acute Chest Syndrome,
Multiple Organ Failure
Biochemical Nature of SCA
Common Treatments
•
Hydroxycarbamide (Hydroxyurea)
•
Blood Transfusions
•
Allogeneic HSCT – only cure for SCA
Emerging Treatments
References
1. Rees, D., Williams, T., & Gladwin, M. (2010). Sickle-cell disease. The Lancet, 376(9757), 2018-2031.
2. Gong, L., Parikh, S., Rosenthal, P., & Greenhouse, B. (2013). Biochemical and immunological mechanisms by which sickle cell
trait protects against malaria. Malaria Journal, 12(317).
3. Bender MA, Douthitt Seibel G. Sickle Cell Disease. 2003 Sep 15 [Updated 2014 Oct 23]. In: Pagon RA, Adam MP, Ardinger HH,
et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
4. Ashley-Koch, A., Yang, Q., & Olney, R. S. (2000). Sickle Hemoglobin (Hb S) Allele and Sickle Cell Disease: A HuGE
Review. American Journal of Epidemiology, 151(9), 839-845.
5. Frenette, P., & Atweh, G. (2007). Sickle Cell Disease: Old Discoveries, New Concepts, and Future Promise. Journal of Clinical
Investigation, 117(4), 850-858.
6. Chakravorty, S., & Williams, T. (2014). Sickle cell disease: A neglected chronic disease of increasing global health
importance. Archives of Disease in Childhood, 100(1), 48-53.
7. George, S., Mitchell, E., Mitchell, N., Eason, T., Fuh, B., & von der Embse, N. (2014). Sickle Cell Disease. Science Scope, 38(4),
33-38.
8. Harrington, D., Adachi, K., & Royer, W. (1997). The high resolution crystal structure of deoxyhemoglobin S. Journal of
Molecular Biology, 272(3), 398-407.
9. Dutta, S., & Goodsell, D. (2003). Hemoglobin. Retrieved March 1, 2015, from
http://www.rcsb.org/pdb/101/motm.do?momID=41
10. The high resolution crystal structure of deoxyhemoglobin S. (1997). Retrieved March 1, 2015, from
http://www.rcsb.org/pdb/explore/explore.do?structureId=2hbs
11. The crystal structure of human deoxyhaemoglobin at 1.74 A resolution. (1984). Retrieved March 1, 2015, from
http://www.rcsb.org/pdb/explore.do?structureId=2HHB
12. Structure of human oxyhaemoglobin at 2.1 A resolution. (1983). Retrieved March 1, 2015, from
http://www.rcsb.org/pdb/explore/explore.do?structureId=1hho