Structure of sickle cell hemoglobin and molecular mechanism of the sickling phenomenon

Precision scale models of sickle cell hemoglobin molecules indicate that the genetic substitution of valine for glutamic acid at the sixth position in the two beta chains allows an intramolecular hydrophobic bond to form. This changes the conformation in such a way as to allow molecular stacking. Results of subjection of Hb S solution to temperature change, to high hydrostatic pressure, and to propane are consistent with the presence of such a bond. Examination of sickled erythrocytes in a magnetic field and in polarized light indicates that the Hb S molecules are aligned in situ. Filaments interpreted as hollow cables of six Hb S monofilaments have been demon-strated by electron microscopy. IN DEOXYGENATED BLOOD from human patients with the hereditary dis-ease sickle cell anemia, the erythrocytes shrink or crumple into cres-centic or holly-leaf shapes. in oxygenated blood the cells assume the normal form of biconcave discs. Over 20 years ago, Pauling (1) sug-gested that the abnormal “sickling ” helmavior might be due to time presence of a chenmicallv different type of hemoglobin molecule which would, on deoxvgenation, aggregate into rods and thereby twist the cell out of shape. in 1950, Perutz and Mitchison (2) found that deoxy-genated sickle-cell hemoglobin (fib S) has a numclm lower solubility than deoxygenated normal hemoglobin (Hi) A) or than eitlmer type of oxy-hemoglobin. Accordingly, they suggested tlmat time sickling phenomeno