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Cellular life is reliant upon rapid and efficient responses to internal and external conditions. The basic molecular events associated with these processes are the structural transitions of the proteins (structural protein allostery) involved. From this view, the human hemoglobin (Hb) molecule (α₂β₂) holds a special position in this field. Hb has two types of αβ interface (i.e., α₁β₁ [and α₂β₂] and α₁β₂ [and α₂β₁]). The latter α₁–β₂ (and α₂–β₁) interface is known to be associated with cooperative O₂ binding, and exhibits principal roles if the molecule goes from its deoxy to oxy quaternary structure. However, the role of the former α₁–β₁ (and α₂–β₂) interface has been unclear for a long time. In this regard, important and intriguing observations have been accumulating. A new role was attributed first as stabilizing the HbO₂ tetramer against acidic autoxidation. That is, the α₁–β₁ (and α₂–β₂) interface produces a conformational constraint in the β chain whereby the distal (E7) histidine (His) residue is tilted slightly away from the bound O₂ so as to prevent proton-catalyzed displacement of O₂^– by a solvent water molecule. The β chains thus acquire pH-dependent delayed autoxidation in the HbO₂ tetramer. The next role was suggested by our studies searching for similar phenomena in normal human erythrocytes under mild heating. Tilting of the distal (E7) His in turn triggered degradation of the Hb molecule to hemichrome, and subsequent clustering of Heinz bodies within the erythrocyte. As Heinz body-containing red cells become trapped in the spleen, it was demonstrated that the α₁–β₁ (and α₂–β₂) interface may exert delicate control of the fate (removal) of its own erythrocyte. Herein we review and summarize the related results and current interpretation of the oxidative behavior of human Hb, emphasizing the correlation between hemichrome emergence and Heinz-body formation, and specifically discuss the new roles assigned to the α₁–β₁ (and α₂–β₂) interface. The α₁–β₁ (and α₂–β₂) interface seems to adequately differentiate between the two types of function (dual roles) from physiological to cellular. Full article

Heinz bodies are intraerythrocytic inclusions of hemichrome formed as a result of hemoglobin (Hb) oxidation. They typically develop in aged red cells. Based on the hypothesis that hemichrome formation is an innate characteristic of physiologically normal Hb molecules, we present an overview of our previous findings regarding the molecular instability of Hb and the formation of hemichrome, as well as recent findings on Heinz body formation within normal human erythrocytes. Human adult Hb (HbO₂ A) prepared from healthy donors showed a tendency to produce hemichrome, even at close to physiological temperature and pH. Recent studies found that the number of Heinz bodies formed in red cells increased with increasing temperature when freshly drawn venous blood from healthy donors was subjected to mild heating above 37 °C. These findings suggest that Hb molecules control the removal of non-functional erythrocytes from the circulation via hemichrome formation and subsequent Heinz body clustering. In this review, we discuss the molecular biosensing mechanisms in the spleen, where hemichrome formation and subsequent Heinz body clustering within erythrocytes play a key role in the removal of aged and damaged red cells from the blood circulation. Full article