HbS (sickle cell hemoglobin) results from a beta-6 Glu→Val substitution. The polymerization of deoxyHbS is the molecular basis of sickling. Which structural feature explains why HbS polymerizes only in the deoxy conformation?

• A In the oxy (R) state, valine-6 is buried in the heme pocket and cannot participate in lateral contacts
• B DeoxyHbS has higher net negative charge at pH 7.4, causing electrostatic aggregation
• C In the deoxy (T) state, the EF corner of the beta-chain exposes a hydrophobic acceptor pocket; Val-6 of an adjacent chain's beta-subunit inserts into this pocket (hydrophobic interaction), nucleating polymer formation ✓
• D Valine-6 forms an intermolecular disulfide bond with cysteine-93 of the adjacent beta-chain in the deoxy state

Explanation

In the deoxy (T) conformation, the EF segment of the beta-globin chain creates a hydrophobic acceptor pocket (formed by phenylalanine-85 and leucine-88). The hydrophobic valine at position 6 (from the mutant beta-chain) fits into this pocket in an adjacent HbS molecule, initiating nucleation of HbS fibers. In the oxy (R) conformation, structural changes close this pocket, so oxyHbS does not polymerize. This explains why sickling is triggered by hypoxia, acidosis (Bohr effect → more deoxyHbS), and dehydration (increasing intracellular HbS concentration, reducing time to polymer nucleation).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.