In sickle cell disease, the primary molecular defect is a point mutation substituting glutamate with valine at position 6 of the beta-globin chain. Which biochemical consequence directly drives sickling?

• A Val6 creates a hydrophobic sticky patch on deoxyHbS that polymerises with a complementary site on adjacent beta-chain ✓
• B Val6 destabilises the alpha1-beta1 interface leading to alpha precipitation
• C Val6 oxidises the heme iron to Fe3+ permanently, forming methemoglobin
• D Val6 activates endogenous phospholipase A2 causing membrane disruption

Explanation

The Val6 residue in deoxyHbS (but not oxyHbS) creates a hydrophobic protuberance that fits into a complementary hydrophobic acceptor site on the EF pocket of an adjacent beta-chain. This non-covalent complementary contact enables HbS molecules to stack into long polymers (fibres) within the deoxygenated red cell, distorting the membrane into the sickle shape. Oxygenation changes HbS conformation, abolishing the sticky patch and reversing polymer formation. The other options describe distinct haemoglobin pathologies unrelated to the polymerisation mechanism.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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