ABSTRACT
There exist several hemoglobin-related diseases (hemoglobinopathies). As large a proportion as perhaps 7% of the world population could be disease carriers. The rst disease that was termed “molecular” is sickle-cell anemia, now known to be caused by a single mutation in the blood protein hemoglobin. As early as the late 1940s, Linus Pauling suggested that the disease was caused by a defective hemoglobin molecule, which was only a few years later was corroborated by experimental observations. Hemoglobin (Hb) has the subunit structure α2β2, and the diseaselinked mutation is that of Glu6 in the β chain to Val, giving rise to sickle-cell Hb, HbS. The Glu6 residue is located at the outside of the three-dimensional structure, and it appears to be critical that this residue should be hydrophilic and not
30.1 Sickle-Cell Anemia and Other Hemoglobin-Related Diseases ................... 395 30.2 Cystic Fibrosis, a Membrane Protein-Related Disease ............................... 398
hydrophobic. In the deoxygenated form, the mutated hemoglobin HbS polymerizes into long brillar structures, a process that leads to precipitation of the protein. Figure 30.1 shows a sketch of how the hydrophobic patch created by the Val residue at the surface of one molecule interacts with another hydrophobic patch, Phe85, on another molecule-thus creating the possibility to form “hydrophobic”
bonds between successive Hb molecules, which gives rise to the polymerization (Figure 30.2). Because the concentration of Hb is very high in red blood cells, the polymerization process is relatively easy to trigger. The Hb precipitation causes collapse of the red blood cells to a “sickle” shape. The cells loose their native elasticity and become rigid, which reduces their mobility through the blood vessels. The clinical manifestation is that of severe anemia.
