Sickled Cells

Hemoglobin misfolding in sickle cell disease results from a single point mutation in the β-globin gene, substituting valine for glutamic acid at position six (HbS).

This small change alters the chemical properties of the hemoglobin subunit, causing deoxygenated HbS molecules to aggregate into rigid, polymerized fibers within the red blood cell.

These polymers distort the cell's normally flexible biconcave shape into a stiff, crescent—or "sickle"—form.

The altered shape compromises the cell's deformability, leading to blockages in small blood vessels (vaso-occlusion), reduced oxygen delivery, and premature hemolysis.

On a molecular level, the hydrophobic valine side chain interacts aberrantly with other hemoglobin molecules, creating a nucleation site for polymer growth that exacerbates this pathological cycle.