Hemoglobin S (HbS) causes sickling because a single amino acid substitution (Glu→Val at position 6 of β-globin) allows HbS molecules to polymerise in the deoxy state. Which structural feature of the Val-6 residue is directly responsible for initiating polymer formation?
- A Valine-6 disrupts the α-helix of the β-globin chain, exposing a heme-binding site that aggregates
- B Glutamate-to-valine change increases the positive charge of HbS, causing electrostatic aggregation
- C Valine-6 eliminates a phosphorylation site, preventing normal red cell deformability
- D Valine-6 creates a hydrophobic 'sticky patch' on the β-chain surface that inserts into a complementary hydrophobic pocket on an adjacent deoxy-HbS molecule ✓
Explanation
The substitution of negatively charged glutamate by hydrophobic valine at β6 exposes a hydrophobic residue on the external surface of the deoxy-HbS molecule. In the deoxy conformation, a complementary hydrophobic acceptor pocket exists between β-chain residues (primarily β88 Leu and β85 Phe). The mutant Val-6 of one HbS molecule fits precisely into this pocket on a neighbouring deoxy-HbS, initiating the nucleation of linear polymer fibres. This polymer distorts the RBC into a sickle shape. In the oxy conformation, the pocket is altered so oxy-HbS does not polymerise, explaining why sickling reverses on oxygenation.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.