Mutations of α- and β-spectrin disrupt the normal predicted structure of the spectrin self-association domain.

(Top pair) Structure of normal spectrin versus spectrin Providence, showing the position of the S→P amino acid replacement at codon β2019 (position 12 in the A helix). Note the predicted severe distortion of this helix, with loss of the β-spectrin pocket into which α-spectrin (helix C) docks. (Bottom pair) A similar analysis revealing the predicted effect of a mutation in codon 28 of α-spectrin (R28S), a mutation that leads to hereditary pyropoikilocytosis. Even though the serine in this mutation is hydrophilic like the residue it replaces (R), the loss of the 2 putative salt bridges formed by the lost arginine (Table 2) destabilizes the self-association binding site. In each model, longitudinal and end-on views are shown. The mutated residue is depicted in space-filled form.