title: Distinct domain responses of R-state human hemoglobins A, C, and S to anions.
abstract: Anionic regulation of hemoglobin (Hb) is of increasing interest for the design of Hb-based oxygen carriers. Even "external" amino-acid substitutions can alter the nature and extent of anionic control. This was shown by evaluation of the anion sensitivities of liganded, R-state, forms of HbA, HbC (beta6 Glu --> Lys) and HbS (beta6 Glu --> Val). The beta6 mutants differ in the anion-sensitivity of their central cavities, alpha1beta2 interfaces, and heme and beta93 Cys environments. The mutant Hbs also exhibit increased anion-dependent oxidation and surface denaturation. Moreover, differential chloride effects on oxygen binding by Hbs C, S compared to HbA occur after R-state stabilization by fluoresceination of beta93 Cys. It is concluded that the "external" substitutions in the mutant Hbs have structural consequences that are propagated to varying extents to other domains as a result of anion binding, and that these anion-dependent changes may underlie mechanisms leading to the observed increase in oxidation propensity and surface denaturation.
authors.affiliation: Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.forename: Celia
authors.initials: C
authors.lastname: Bonaventura
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Nagel
authors.forename: Rhoda Elison
authors.initials: RE
authors.lastname: Hirsch
mesh_terms: D000838:Anions / Q000494:pharmacology; D001665:Binding Sites; D011232:Chemical Precipitation; D002712:Chlorides / Q000494:pharmacology; D006441:Hemoglobin A / Q000737:chemistry / Q000235:genetics; D006444:Hemoglobin C / Q000737:chemistry / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000737:chemistry / Q000235:genetics; D006454:Hemoglobins / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010100:Oxygen; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D000838:Anions; D002712:Chlorides; D006451:Hemoglobin, Sickle; D006454:Hemoglobins; D006444:Hemoglobin C; D006441:Hemoglobin A; D010100:Oxygen