Hemoglobin Hirose, a human hemoglobin variant with a substitution at the alpha1beta2 interface. Subunit dissociation and the equilibria and kinetics of ligand binding.

Sasaki, Jun; Imamura, Takashi; Yanase, Toshiyuki

doi:10.1016/s0021-9258(17)38273-x

Cited by 41 publications

(6 citation statements)

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“…31 Hemoglobin with the following mutation, βW37S, resulted in an increased oxygen affinity and reduced cooperativity, thus indicating involvement of βTrp37 residue in oxygen binding. 32 In HbA deoxy , the carbonyl group of βVal34 is bonded to the side chain of αArg141, whereas in HbA oxy , αArg141 appears to be free. 16 It was also reported that in HbA oxy βArg40 forms a hydrogen bond with αThr41.…”

Section: ■ Introductionmentioning

confidence: 99%

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

et al. 2012

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Glutathionyl hemoglobin, a post-translationally modified form of hemoglobin, has been reported to serve as a marker of oxidative stress in several clinical conditions. This modification causes perturbations in the hemoglobin functionality by increasing oxygen affinity and reducing cooperativity. Moreover, glutathionylation of sickle hemoglobin was reported to lead to a significant reduction in the propensity of sickling of erythrocytes. The root cause of the above functional abnormality is not known in detail, as the crystal structure of the molecule is yet to be discovered. In this study, we investigated the effects of glutathionylation on quaternary structure of hemoglobin using hydrogen/deuterium exchange (H/DX) based mass spectrometry. H/DX kinetics of nine peptides from α and β globin chains of hemoglobin were analyzed to understand the conformational change in deoxy to oxy transition of normal hemoglobin and structural perturbations associated with glutathionylation of oxy hemoglobin. Significant structural changes brought about by the glutathionylation of oxy hemoglobin were observed in the following regions of globin chains: β86-102, β1-14, α34-46, β32-41, β130-146, β115-129, β73-81. Isotope exchange kinetics monitored through mass spectrometry is a useful technique to understand structural perturbation on post-translational modification of proteins in solution phase.

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Section: ■ Introductionmentioning

confidence: 99%

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

et al. 2012

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“…In other cases, the loss of relatively few R1β2 interactions has more significant consequences (5,6), with mutations of Trp37(C3)β being among the most disruptive. Previous studies (7)(8)(9)(10)(11)(12) have shown that mutations at Trp37-(C3)β severely destabilize the R1β2 interface, and the altered functional properties of these mutants have been attributed largely to the formation of Rβ dimers. However, the accompanying papers (13)(14)(15) show that a large shift in the tetramer-to-dimer equilibrium is not sufficient to account for the wide range of altered functional properties of the mutants βW37Y, 1 βW37A, βW37E, and βW37G.…”

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confidence: 99%

High-Resolution Crystal Structures of Human Hemoglobin with Mutations at Tryptophan 37β: Structural Basis for a High-Affinity T-State^,

et al. 1998

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The high-resolution X-ray structures of the deoxy forms of four recombinant hemoglobins in which Trp37(C3)beta is replaced with Tyr (betaW37Y), Ala (betaW37A), Glu (betaW37E), or Gly (betaW37G) have been refined and analyzed with superposition methods that partition mutation-induced perturbations into quaternary structure changes and tertiary structure changes. In addition, a new cross-validation statistic that is sensitive to local changes in structure (a "local Rfree" parameter) was used as an objective measure of the significance of the tertiary structure changes. No significant mutation-induced changes in tertiary structure are detected at the mutation site itself for any of the four mutants studied. Instead, disruption of the intersubunit contacts associated with Trp37(C3)beta results in (1) a change in quaternary structure at the alpha1beta2 interface, (2) alpha subunit tertiary structure changes that are centered at Asp94(G1)alpha-Pro95(G2)alpha, (3) beta subunit tertiary structure changes that are located between residues Asp99(G1)beta and Asn102(G4)beta, (4) increased mobility of the alpha subunit COOH-terminal dipeptide, and (5) shortening of the Fe-Nepsilon2His(F8) bond in the alpha and beta subunits of the betaW37G and betaW37E mutants. In each case, the magnitude of the change in a particular structural parameter increases in the order betaW37Y < betaW37A < betaW37E approximately betaW37G, which corresponds closely to the degree of functional disruption documented in the preceding papers.

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“…In normal HbA 0 , β37 tryptophan interacts with arginine (RR92), aspartate (RD94), and proline (RP95) residues of the R FG corner and also with a tyrosine (RY140) from the N-terminal peptide (Baldwin & Chothia, 1979). Properties of the naturally occurring β37 mutants Rothschild (βW37R) (Sharma et al, 1980;Turner et al, 1992), Hirose (βW37S) (Sasaki et al, 1978, Turner et al, 1992, and Howick (βW37G) (Brittain, 1994;Owen et al, 1993), as well as the recombinant Hbs βW37T (Vallone et al, 1996) and βW37F (Ishimori et al, 1992), showed that replacement of Trp results in significantly increased tetramer dissociation in both the deoxygenated and oxygenated states. For example, the Hb Hirose tetramer is 1500 times less stable than HbA 0 in the deoxy state and 100 times less stable in the oxy state (Turner et al, 1992).…”

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confidence: 99%

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

et al. 1998

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In human hemoglobin (Hb) the beta37 tryptophan residue (betaW37), located at the hinge region of the alpha1beta2 interface, forms many contacts with alpha subunit residues of the opposite dimer, in both the T and R quaternary structures. We have carried out equilibrium O2 binding studies on a series of recombinant Hbs that have mutations at this residue site: betaW37Y, betaW37A, betaW37G, and betaW37E. Binding isotherms measured at high concentrations of these mutants were found to be shifted toward increased affinity and decreased cooperativity from that of the normal HbA0 tetramer. Analysis of these binding isotherms indicated that amino acid substitutions at the beta37 position could both destabilize the tetrameric form of the mutants relative to their constituent dimers and also alter cooperativity of the intact tetrameric species. These alterations from wild-type function are dependent on the particular side chain substituted, with the magnitude of change increasing as Trp is substituted by Tyr, Ala, Gly, and Glu. The dimer to tetramer assembly free energy of deoxy-betaW37E, the most perturbed mutant in the series, was measured using analytical gel chromatography to be 9 kcal/tetramer less favorable than that of deoxy HbA0. Stabilizing the betaW37E tetramer by addition of IHP, or by cross-linking at the alphaK99 positions, does not restore normal O2 binding behavior. Thermodynamic parameters of all the mutants were found to correlate with their CO binding rates and with their high-resolution X-ray crystal structures (see accompanying papers: Kwiatkowski et al. (1998) Biochemistry 37, 4325-4335; Peterson & Friedman (1998) Biochemistry 37, 4346-4357; Kavanaugh et al. (1998) Biochemistry 37, 4358-4373].

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Hemoglobin Hirose, a human hemoglobin variant with a substitution at the alpha1beta2 interface. Subunit dissociation and the equilibria and kinetics of ligand binding.

Cited by 41 publications

References 38 publications

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

High-Resolution Crystal Structures of Human Hemoglobin with Mutations at Tryptophan 37β: Structural Basis for a High-Affinity T-State^,

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

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Hemoglobin Hirose, a human hemoglobin variant with a substitution at the alpha1beta2 interface. Subunit dissociation and the equilibria and kinetics of ligand binding.

Cited by 41 publications

References 38 publications

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

Glutathionylation Induced Structural Changes in Oxy Human Hemoglobin Analyzed by Backbone Amide Hydrogen/Deuterium Exchange and MALDI-Mass Spectrometry

High-Resolution Crystal Structures of Human Hemoglobin with Mutations at Tryptophan 37β: Structural Basis for a High-Affinity T-State,

Thermodynamic Studies on the Equilibrium Properties of a Series of Recombinant βW37 Hemoglobin Mutants

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High-Resolution Crystal Structures of Human Hemoglobin with Mutations at Tryptophan 37β: Structural Basis for a High-Affinity T-State^,