Most of hereditary elliptocytosis (HE) cases are related to a spectrin dimer (SpD) self-association defect. The severity of haemolysis is correlated with the extent of the SpD self-association defect, which itself depends on the location of the mutation regarding the tetramerization site. This site is presumed to involve the first C helix of the α chain and the last two helices, A and B, of the β chain to reconstitute a triple helical structure (A, B and C), as observed along spectrin. Using recombinant peptides, we demonstrated that the first C helix of the α chain and the last two helices of the β chain alone are not sufficient to establish interactions, which only occurred when a complete triple-helical repeat was added to each partner. One adjacent repeat is necessary to stabilize the conformation of both N- and C-terminal structures directly involved in the interaction site and is sufficient to generate a binding affinity similar to that observed in the native molecule. Producing peptides carrying a βHE mutation, we reproduced the tetramerization defect as observed in patients. Therefore, the βW2024R and βW2061R mutations, which replace the invariant tryptophan and a residue located in the hydrophobic core, respectively, affect α–β interactions considerably. In contrast, the βA2013V mutation, which modifies a residue located outside any presumed interacting regions, has a minor effect on the interaction.

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