Conjugal interactions between consenting spectrins: predicting which mutations will lead to hereditary hemolytic anemias

The erythrocyte membrane skeleton comprises α/β spectrin heterodimers that must associate into elongated heterotetramers (and higher oligomers) in order to span between actin-rich junctional complexes. Mutations leading to weakened or flawed spectrin self-association result in hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP), which in certain homozygous states can be lethal. Because such mutations have been mapped to either the NH₂-terminus of α-spectrin or the COOH-terminus of β-spectrin, the polypeptide's self-association domain has been hypothesized to reside within these termini. Experimental support for this hypothesis is already considerable.

Not surprisingly, some mutations within the spectrin self-association domain do not cause hemolytic disease. In an effort to enable prediction of the hemolytic consequences of novel point mutations within these self-association sequences, Zhang and colleagues (page1645) have undertaken to model the interaction using energy minimization and molecular dynamics computational strategies. As a starting point, the authors assumed that the docking interface would consist of 1 α-helix from the NH₂-terminus of α-spectrin nestled between 2 antiparallel α-helices from the COOHterminus of β-spectrin. This assumption was strongly supported by previous experimental data and by analogy with the known triple helical motif that constitutes most of the structure of both α and β spectrin. Thus the self-association site has been envisioned to mimic the coiled-coil triple helix of the basic spectrin repeat.

Confirmation of the derived model derives from multiple observations. First, the computational methodology allowed prediction of the known crystal structure of the 14th repeat unit of Drosophilaα-spectrin. Second, the modeling strategy computed a credible structure for the self-association complex of human spectrin that closely resembled the structure of the spectrin repeats, despite substitution of over 70% of the residues in Drosophilaspectrin with frequently nonconservative amino acids from human spectrin. And most significantly, the altered structures that were observed upon modeling 17 of the known mutant forms of human spectrin predicted conformational deformations whose magnitude correlated strongly with the severity of the consequent hereditary hemolytic diseases.

So where do we go from here? First, it would make sense to test whether other mutants not provided by nature yield a hemolytic anemia whose severity is predicted by the modeled degree of structural distortion. Second, it would be very satisfying to exploit the methodology to design therapeutic agents that might repair the flawed self-association interactions in the hemolytic anemias. And finally, where possible, similar methods should be applied to other membrane structural interactions with the ultimate goal of developing a predictive model of global membrane morphology and mechanical stability.