赤血球膜蛋白質の構造・機能と疾患病態

Abstract

The investigation of red cell anion exchange protein, band 3 has been at the center of two fundamental questions on functions of membrane proteins : how they regulate cell morphology, and how they regulate homeostasis in the cell and throughout the whole organism. Our recent studies on bovine hereditary band 3 deficiency, a novel disorder inherited in an autosomal dominant mode in which homozygous animals totally lack band 3 due to a nonsense mutation Arg664 → stop, have addressed the importance of band 3 in red cell morphology and homeostasis. The animals with total lack of band 3 had red cells that were also deficient in other major membrane skeletal proteins, resulting in a distorted and disrupted membrane skeletal network. Their red cell membranes, therefore, were extremely unstable and showed a continuous loss of surface area, leading to spherocyte formation and anemia. The decreased 4.1a/4.1b ratio implicated a high rate of hematopoiesis compensatory to survive. Rapid anion exchange sensitive to stilbene disulfonate was completely absent in band 3-deficient cells. The animals had slight acidosis and their blood bicarbonate concentration and total CO2 were lower than control levels but within a normal range, suggesting that there are alternate or multiple strategies for CO2 and pH homeostasis. These observations demonstrate that band 3 indeed contributes to red cell membrane organization, CO2 transport, and acid-base homeostasis, but it is not always essential. A putative dominant negative effect of the mutant band 3 protein on expression of functional band 3 is also discussed.