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 (α
2β
2) holds a special position in this field. Hb has two types of αβ interface (
i.e., α
1β
1 [and α
2β
2] and α
1β
2 [and α
2β
1]). The latter α
1–β
2 (and α
2–β
1) interface is known to be associated with cooperative O
2 binding, and exhibits principal roles if the molecule goes from its deoxy to oxy quaternary structure. However, the role of the former α
1–β
1 (and α
2–β
2) 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 HbO
2 tetramer against acidic autoxidation. That is, the α
1–β
1 (and α
2–β
2) interface produces a conformational constraint in the β chain whereby the distal (E7) histidine (His) residue is tilted slightly away from the bound O
2 so as to prevent proton-catalyzed displacement of O
2– by a solvent water molecule. The β chains thus acquire pH-dependent delayed autoxidation in the HbO
2 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 α
1–β
1 (and α
2–β
2) 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 α
1–β
1 (and α
2–β
2) interface. The α
1–β
1 (and α
2–β
2) interface seems to adequately differentiate between the two types of function (dual roles) from physiological to cellular.
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