Isolated beta‐globin chains reproduce, in normal red cell membranes, the defective binding of spectrin to alpha‐thalassaemic membranes

Alpha‐thalassaemic erythrocytes develop a specific membrane skeletal defect that is manifest as a loss of normal spectrin‐binding sites on the inner surface of the thalassaemic membranes. To test whether this lesion could be caused by the excess free beta‐globin chains that accumulate in alpha‐thalassaemic red cells, we incubated normal red cell membranes with native, haem‐containing alpha or beta globin chains or with haemoglobin A. Spectrin‐depleted inside‐out membrane vesicles (IOVs) derived from membranes incubated with beta‐globin chains bound only 9 ± 3% as much spectrin as IOVs from control membranes incubated with bovine serum albumin. In contrast, IOVs from membranes incubated with alpha‐globin chains or haemoglobin A were nearly normal (79 ± 3% and 86 ± 5% of controls, respectively). This differential effect of globin chains was not seen when membranes were first transformed into spectrin‐depleted IOVs and then incubated with the isolated globin chains. Under these conditions, both alpha and beta globin chains reduced the spectrin‐binding capacity of the IOVs by approximately 45% (alpha 46 ± 7%, beta 43 ± 6%) whereas haemoglobin A had no effect. Unlike IOVs, spectrin isolated from membranes exposed to alpha or beta globin chains bound normally to IOVs and to actin (in the presence of protein 4.1). These studies show that isolated beta‐globin chains (but not alpha‐globin chains) can produce a spectrin‐binding defect in normal red cell membranes similar to that seen in alpha thalassaemia. The existence of similar defects in the membrane skeletons of red cells from other diseases with unstable beta globins suggests a common pathophysiology for the premature destruction of these cells.