alpha Chain mutations with opposite effects on the gelation of hemoglobin S.

The preparation of three hemoglobin tetramers containing the hemoglobin S mutation at beta 6 and an additional one at alpha 6, alpha 47, and alpha 75 is described. The effect of the substitutions in the alpha chains on polymerization was investigated by the equilibrium solubility of the gels as well as the abrupt change in oxygen affinity associated with the onset of gelation. Substitution of a histidine for aspartic acid at alpha 47 causes a marked inhibition of polymerization. This inhibition probably results from tetramers which carry the two substitutions on the same alpha beta dimer. By contrast, the introduction of a tyrosine at alpha 75 and an alanine at alpha 6 have the opposite effect and are the first examples of alpha chain mutations which potentiate the gelation of Hb S. The molecular mechanisms responsible for the effects of the mutations on the self-association of Hb S are discussed.