title: Was the loss of the D helix in alpha globin a functionally neutral mutation?
abstract: Proteins in the globin family are found in a variety of species from bacteria to man. From the many globin sequences known, evolutionary trees have been constructed showing that alpha and beta globins diverged from a common ancestor between 425 and 500 million years ago, after vertebrate species had appeared and roughly when sharks and bony vertebrates diverged. The alpha and beta globins assemble to form tetrameric haemoglobin, alpha 2 beta 2, which can switch between quaternary states having high and low oxygen affinity. This allows the protein to bind oxygen cooperatively and therefore efficiently transport oxygen from the lungs to respiring tissues. The alpha and beta globins have closely related tertiary structures, being alpha-helical proteins with similar haem-binding sites. Most globins consist of eight helices, designated A to H from the N terminus, connected by short nonhelical segments, but all known vertebrate alpha globins lack a D helix. Because the loss of this helix by alpha globin occurred shortly before tetrameric haemoglobin appeared, it might be a functionally important mutation required for a tetramer assembly or allostery. We have now tested this idea by engineering human haemoglobins containing beta subunits without a D helix and alpha subunits with a D helix. Both of these mutations have little effect on the oxygen-binding properties of the molecule. Thus it is possible that deletion of the D helix in the alpha subunit was caused by a neutral mutation.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: N H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: D T
authors.initials: DT
authors.lastname: Shih
authors.forename: D
authors.initials: D
authors.lastname: Looker
authors.forename: J
authors.initials: J
authors.lastname: Tame
authors.forename: K
authors.initials: K
authors.lastname: Nagai
mesh_terms: D004926:Escherichia coli / Q000235:genetics; D005914:Globins / Q000737:chemistry*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011487:Protein Conformation; D014162:Transfection
chemical_list: D006454:Hemoglobins; D005914:Globins; D010100:Oxygen