Question

HbS, the variant of hemoglobin responsible for sickle-cell anemia, aggregates into long chains in aqueous, biological conditions (pH 7.4, 37^oC, some salt and buffer present).

1. Explain this phenomenon from a molecular point of view. Why does it form chains, not globular aggregates?

2. Why is this phenomenon unsurprising to biochemists familiar with the details of protein folding?

Answer 1

Normal hemoglobin (Hb) is made up of 2 alpha subunits and 2 beta subunits. In sickle hemoglobin (HbS) a missense mutation results in substitution of glutamicacid acid, a hydrophilic amino acid with valine, a hydrophobic amino acid on the surface of HbS in the sixth position of beta globin chain. When Hb is deoxygenated i.e when it is in venous capillaries the hydrphobic valine forms hydrophobic interactions with other hydrophobic amino acids on the surface of beta globin chain of another deoxy-HbS molecule. This results in formation and lengthening of polymer in helical fibres which when grouped together stiffen and induce the characteristic sickle RBC. Dysregulation of K-Cl co-transport system and Ca-dependent K channels leads to potassium loss and cellular dehydration thus favouring deoxy-HbS polymerisation.

The phenomena of HbS polymerisation is not unsuprising to biochemists because many time proteins that are folded improperly, may impact the health of the cell in spite of the function of the protein. When proteins fail to fold into functional structural form this results in misfolded protein which are the contorted into various shapes that are unfavourable to the cellular environment. This type of misfolding guides the protein to formation of large aggregates which are accumulated inside the cell leading to various disorders.