New Roles Assigned to the α1–β1 (and α2–β2) Interface of the Human Hemoglobin Molecule from Physiological to Cellular

Abstract

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.