STRUCTURAL BASES OF THE INHIBITORY EFFECTS OF HEMOGLOBIN-F AND HEMOGLOBIN-A-2 ON THE POLYMERIZATION OF HEMOGLOBIN-S

It was previously found that the inhibitory effect of [human] Hb F [fetal Hb] on the polymerization of Hb S [sickle cell anemia] proceeds via the formation of asymmetrical hybrid tetramers of the type .alpha.2.beta.s.gamma.. In this study examination of the gelling properties of binary mixtures of Hb S and several Hb variants showed that, among the .gamma. chain amino acid residues that differ from those of the .beta. chain, residues .gamma.80 (EF4) and .gamma.87 (F3) are at least partly responsible for this inhibition. Mixing Hb A2(.alpha.2.delta.2) with Hb S strongly inhibited gelling to an extent similar to that seen with Hb S/Hb F mixtures. This inhibition was attributable to amino acid differences between the .delta. and .beta. chain sequences at positions .delta.22 (B4) and .delta.87 (F3). Residues 22, 80 and 87 of the .beta. chain appeared to be involved in intermolecular contact sites that stabilize the deoxy Hb S polymers.