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Spectrin self-association site: characterization and study of beta-spectrin mutations associated with hereditary elliptocytosis.

Abstract : 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 alpha chain and the last two helices, A and B, of the beta 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 alpha chain and the last two helices of the beta 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 betaHE mutation, we reproduced the tetramerization defect as observed in patients. Therefore, the betaW2024R and betaW2061R mutations, which replace the invariant tryptophan and a residue located in the hydrophobic core, respectively, affect alpha-beta interactions considerably. In contrast, the betaA2013V mutation, which modifies a residue located outside any presumed interacting regions, has a minor effect on the interaction.
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https://www.hal.inserm.fr/inserm-00284779
Contributor : Gaël Nicolas <>
Submitted on : Tuesday, June 3, 2008 - 4:51:12 PM
Last modification on : Tuesday, July 21, 2020 - 3:58:48 AM
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  • HAL Id : inserm-00284779, version 1
  • PUBMED : 9576854

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Gaël Nicolas, Sophie Pedroni, Catherine Fournier, Huguette Gautero, Constantin Craescu, et al.. Spectrin self-association site: characterization and study of beta-spectrin mutations associated with hereditary elliptocytosis.. Biochemical Journal, Portland Press, 1998, 332 ( Pt 1), pp.81-9. ⟨inserm-00284779⟩

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