Spectrin cagliari. an Ala–>Gly substitution in helix 1 of beta spectrin repeat 17 that severely disrupts the structure and self-association of the erythrocyte spectrin heterodimer

The spectrin tetramer, the principal structural element of the red cell membrane skeleton, is formed by stable head-to-head self-association of two spectrin heterodimers. The self-association site appears to be formed by interactions between helices 1 and 2 of beta spectrin repeat 17 of one dimer wi...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 268; no. 30; pp. 22656 - 22662
Main Authors:	Sahr, K.E., Coetzer, T.L., Moy, L.S., Derick, L.H., Chishti, A.H., Jarolim, P, Lorenzo, F, Miraglia del Giudice, E, Iolascon, A, Gallanello, R
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Elsevier Inc 25-10-1993 American Society for Biochemistry and Molecular Biology
Subjects:	Alanine Amino Acid Sequence Analytical, structural and metabolic biochemistry Antibodies, Monoclonal Base Sequence Biological and medical sciences DNA Primers Erythrocyte Membrane - metabolism Exons Female Fundamental and applied biological sciences. Psychology Glycine Glycoproteins Humans Macromolecular Substances Male Microscopy, Electron Molecular Sequence Data Oligonucleotides, Antisense Pedigree Point Mutation Polymerase Chain Reaction Protein Structure, Secondary Proteins Spectrin - chemistry Spectrin - genetics Spectrin - ultrastructure Human Spectrin Self association Transmission electron microscopy Glycoproteins Property structure relationship Mutation Oligomer
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Summary:	The spectrin tetramer, the principal structural element of the red cell membrane skeleton, is formed by stable head-to-head self-association of two spectrin heterodimers. The self-association site appears to be formed by interactions between helices 1 and 2 of beta spectrin repeat 17 of one dimer with helix 3 of alpha spectrin repeat 1 of the other dimer to form two combined alpha-beta triple-helical segments. The head of the heterodimer appears to involve similar intradimer interactions. We describe the first example of an amino acid substitution in helix 1 of this combined alpha-beta triple-helical segment, which, although relatively minor, profoundly impairs tetramer formation. Strikingly, low angle rotary shadowing electron microscopy of isolated spectrin dimers reveals that this mutation also severely disrupts the head of the heterodimer causing it to be open. Following linkage studies which were most consistent with a beta spectrin gene mutation, a nucleotide change was identified in codon 2018, resulting in an Ala–>Gly substitution in the first helical domain of beta spectrin repeat 17. Because glycine is a strong helix breaker, this change is predicted to disrupt the conformation of this helical domain. Our results indicate that this helical domain must play direct roles in the alpha-beta interdimer interactions that form the self-association site of the tetramer and in the alpha-beta intradimer interactions at the head of the heterodimer.
Bibliography:	ObjectType-Case Study-3 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-2
ISSN:	0021-9258 1083-351X
DOI:	10.1016/S0021-9258(18)41578-5