Hb Chesapeake has an alpha-92 Arg→Leu mutation at the alpha1-beta2 interface (the switching interface). This Hb shows increased O2 affinity (left-shifted ODC) and erythrocytosis. What is the molecular mechanism?

• A The mutation increases heme-iron affinity for O2 by altering the proximal histidine geometry
• B The leucine mutation prevents 2,3-BPG binding to the central cavity of deoxyhemoglobin
• C The mutation causes dissociation of beta-dimers from alpha-dimers, creating beta-4 tetramers with high O2 affinity
• D The interface mutation destabilizes the T (deoxy) state by weakening the T-state constraints, shifting the equilibrium toward the R (oxy) state even at lower O2 tensions ✓

Explanation

The alpha1-beta2 (also called alpha1-beta2 switching) interface undergoes a critical 15° rotation when hemoglobin transitions from R (oxy) to T (deoxy) state. Arg-92alpha normally forms a critical T-state salt bridge/hydrogen bond at this interface, stabilizing the tense (low-affinity) deoxy conformation. The Arg→Leu mutation eliminates this ionic interaction, destabilizing the T state. The equilibrium shifts toward the R (high-affinity) state, increasing O2 affinity (left-shifted curve). The high-affinity Hb delivers less O2 to tissues → EPO stimulation → secondary erythrocytosis. Hb Kempsey and Hb Yakima have similar mechanisms.

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

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