Yoshiaki Sugawara, Yuki Shigemasa, Yuko Hayashi, Yoko Abe, Ikumi Ohgushi and Eriko Ueno
The human hemoglobin (Hb) molecule (α2β2) has two types of α–β interface (i.e., α1–β1[and α2–β2] and α1–β2[and α2–β1]). The latter α1–β2(and α2–β1) interface is associated with cooperative O2 binding, and exhibits principal roles if the molecule goes from its deoxygenated to oxygenated quaternary structure. 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, so that a new gaze can be focused on the α1–β1(and α2–β2) interface. Our most recent findings suggest that the α1–β1(and α2–β2) interface may exert delicate control of the intrinsic tilting capability of the distal (E7) His residues (i.e., α58His (E7) in the α chain and β63His (E7) in the β chain) depending on internal and external conditions of the erythrocyte to lead to degradation of Hb to hemichrome, and subsequent clustering of Heinz bodies within the erythrocyte. In the spleen, rigid intra-erythrocytic hemichrome inclusions (Heinz bodies) act as “sticking points”, so Heinz body-containing red cells become trapped and undergo hemolysis. In this article, we first provide our necessary basic experimental findings that led us to grasp molecular biosensing mechanisms inherent in human erythrocytes for the appreciation of aging and determination of their lifespan, and summarize their roles in physiology. We then discuss how these accomplishments contribute to deeper understanding of clinical aspects of drug-induced hemolytic anemia, defects in the intra-erythrocytic reducing system and unstable Hb disease, in which the mechanisms for acute hemolytic crisis cannot be explained on the basis of conventional views.
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