Sickle cell

 

Some background

Sickle cell disease holds a special position as the first disease for which an underlying molecular cause was identified--by Linus Pauling in 1945. The consequences of the simple replacement of a charged amino acid (Glu beta 6) with a hydrophobic, neutral Val are far ranging, and understanding their details remains a vital area of current investigation.

Structure

The amino acid replacement leads to the formation of long, multistranded structures. The structures utilize a double stranded motif, which is also seen in crystals of HbS. The double strand involves a variety of intermolecular contacts, but oddly enough only one of the replaced amino acids is involved in an up-down contact along the polymer. Unlike the crystal, the fibrous double strand found in solutions or cells is twisted, and the identification of the contacts between Hb molecules relies on understanding how the twist occurs and affects the crystal contacts.

The predominant structure seen in solutions or cells is composed of seven double strands: six wrapped around a central double strand The interplay of twist and contact energy has been proposed as the limiting feature on the 14 strand polymer. In the diagram below, each molecule of hemoglobin (MW 64,000) is shown as a sphere.