Molecular diseases

At this point we have studied myoglobin and hemoglobin with a pretty high level of detail. As I said at the begining of these series of lectures, a lot of people have done a lot of studies on these two oxygen storage and transport proteins, and a lot about them is known, from their structure to their genetics.

Several studies have shown that there are a lot of variants of myoglobin and hemoglobin for a certain ogranism. These variants are proteins in which there are some variations in the primary structure of the protein subunits. They originate from mutations on the genes that encode their sequence, and they are hereditary, i.e., they are transmited from parents to children. Almost 300 different variants of hemoglobin are known, and most are pretty much as good as the real McCoy.

However, there are certain mutations that cause severe diseases because they either disrupt the normal binding of oxygen to the protein, or due to conformational changes in the molecule that affect their dynamics. Perhaps the best know of these molecular diseases is sickle cell anemia.

Sickle cell anemia

When we discussed hemoglobin we did not mention how is that the different subunits come together to form the b₂a₂ tetramers. There is an equilibrium between the free a and b subunits, ab dimers, and the b₂a₂ tetramers in solution:

In normal hemoglobin, the equilibrium, which is pretty displaced towards the right, stays put at this stage.

In sickle cell anemia, the b chains of hemoglobin have a singe amino acid mutation (substitution) at position 6. The glutamate residue that is normally at this position is mutated to a valine residue:

Although this amino acid is far from the binding site of oxygen and does not affect the O₂ affinity of the protein, it creates a hydrophobic patch on the surface of the b subunits, also known as a 'sticky end' on the b subunits. This hydrophibic protrussion unfortunately fits right into a hydrophobic pocket in the other side of the b chain. Since in water we tend to group hydrophobic areas together to minimize unfavourable interactions, they will come together and 'stick' to each other:

This causes the equilibrium to keep going to the formation of relativelly long fiber-like aggregates of hemoglobin tetramers. These fiber agreggate furhter side by side into large rod-like structures, which span accross the red cells. They stretch the red cell and make them adopt a characteristic sickled shape. After a while, the tensil strain on the walls of the red cells causes them to burst, and these causes anemia, because there is a depletion of oxygen carrying red cells.

As you probably know, sickle cell anemia is more common in the US among the African American population, and around the world, it usually happens among populations originating in tropical areas. So, why has a mutation that is so detrimental to the normal life is still around? Usually, mutations that are unfavourable are phased out from the genetic pool. Not with sickle cell anemia. The reason is that in tropical areas there is also a high incidence of malaria, a parasitic disease caused by the bug Plasmodium falciparium, which is carried by the Anophelesmosquitoe. In one of the stages of the life of the parasite, it depends on the red cell (actually, on hemoglobin) to survive. Individuals with sickle cell genes (and therefore fragile red cells) battle the parasite by destroying its 'home' in the body. Kind of a Machiavelously rotten deal, but...

Prepared by Guillermo Moyna, 1999.